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VORAPAXAR

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Vorapaxar is a protease activated receptor-1 (PAR-1) antagonist inhibiting thrombin-mediated platelet aggregation.

Specific Substances

    1) Vorapaxar Sulfate
    2) SCH-530348
    3) CAS 618385-01-6 (vorapaxar)
    4) CAS 705260-08-8 (vorapaxar sulfate)
    1.2.1) MOLECULAR FORMULA
    1) C29H33FN2O4.H2SO4 (vorapaxar sulfate) (Prod Info ZONTIVITY(TM) oral tablets, 2014)

Available Forms Sources

    A) FORMS
    1) Vorapaxar is available as 2.08 mg film-coated tablets (equivalent to 2.5 mg vorapaxar sulfate) (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    B) USES
    1) Vorapaxar inhibits thrombin-mediated platelet aggregation and is indicated to reduce thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease, and who do not have a history of stroke, transient ischemic attack, or intracranial hemorrhage (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    2) Vorapaxar should be administered with aspirin and/or clopidogrel according their indications or standard of care. There is no experience with administration of vorapaxar as monotherapy and limited experience coadministered with other antiplatelet agents (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Vorapaxar inhibits thrombin-mediated platelet aggregation and is indicated to reduce thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease, and who do not have a history of stroke, transient ischemic attack, or intracranial hemorrhage.
    B) PHARMACOLOGY: Vorapaxar inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. Vorapaxar reversibly inhibits protease-activated receptor-1 (PAR-1), although its long half-life makes it effectively irreversible. Vorapaxar does not appear to affect coagulation parameters, nor does it inhibit platelet aggregation due to adenosine diphosphate, collagen, or thromboxane mimetic activities.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effect reported is bleeding, including life-threatening and fatal bleeding.
    2) INFREQUENT: Adverse effects that were reported less frequently include anemia, depression, dermatological reactions (ie, rashes, eruptions, and exanthemas), iron deficiency, retinopathy, and diplopia and other oculomotor disturbances.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, overdose has not been reported. It is anticipated that overdose effects are an extension of adverse effects observed with therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Vorapaxar is classified as FDA pregnancy category B. There have been no embryo/fetal toxicities, malformations, or maternal toxicities in rats and rabbits exposed to vorapaxar during gestation 56 times and 26 times, respectively, the human systemic exposure at the recommended human dose.

Laboratory Monitoring

    A) Monitor CBC with differential and platelet count following an overdose.
    B) Monitor for clinical evidence of bleeding.
    C) Monitor serial hemoglobin and hematocrit in patients with suspected bleeding.
    D) Obtain a head CT in patients with suspected intracranial bleeding.
    E) Routine serum coagulation profiles are not clinically useful in determining vorapaxar effect or toxicity in overdose. However, they may be useful to determine baseline coagulation deficiencies from pre-existing disease and/or coagulopathy caused by co-ingestions.
    F) Serum vorapaxar concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) Treatment is symptomatic and supportive. There is no known treatment to reverse the antiplatelet effect of vorapaxar. Platelet transfusion is not expected to be beneficial. Monitor serial CBC with differential. Whole blood or packed red blood cell transfusions as needed for moderate or severe bleeding.
    B) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    C) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe bleeding, including intracranial and gastrointestinal bleeding.
    D) ANTIDOTE
    1) None
    E) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable. The duration of observation is unknown as vorapaxar has an effective half-life of 3 to 4 days and an apparent terminal elimination half-life of 8 days.
    3) ADMISSION CRITERIA: Patients with moderate or severe bleeding, requiring therapeutic intervention, should be admitted.
    4) CONSULT CRITERIA: Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom diagnosis is unclear. A hematology consult should also be considered.
    G) PITFALLS
    1) When managing a suspected vorapaxar overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose may be similar to reported side effects of the medication.
    H) PHARMACOKINETICS
    1) Bioavailability of is approximately 100%. Protein binding is at least 99% and the mean volume of distribution is 424 liters. Vorapaxar is metabolized in the liver via cytochrome P450 3A4 and 2J2 enzymes, with M20-vorapaxar as the major active metabolite in circulation and M19-vorapaxar as the major metabolite recovered upon excretion. Approximately 25% of a radiolabeled dose is recovered in urine, as metabolites, with no unchanged drug detected in urine, and 58% of an administered radiolabeled dose is recovered in feces. The effective half-life is 3 to 4 days and the apparent terminal half-life is approximately 8 days.
    I) PREDISPOSING CONDITIONS
    1) The risk of intracranial hemorrhage is increased in patients with a history of stroke, transient ischemic attacks, or intracranial hemorrhage; vorapaxar is contraindicated in these patient populations.
    J) DIFFERENTIAL DIAGNOSIS
    1) Other agents (ie, anticoagulant therapy, aspirin therapy, other antiplatelet agents (ie, clopidogrel, prasugrel) or conditions that may cause an increase in bleeding tendencies.

Range Of Toxicity

    A) TOXICITY: Toxic dose has not been established. Overdose has not been reported at the time of this review.
    B) THERAPEUTIC DOSE: ADULTS: The recommended dose is 2.08 mg orally once daily. CHILDREN: Safety and efficacy in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Vorapaxar inhibits thrombin-mediated platelet aggregation and is indicated to reduce thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease, and who do not have a history of stroke, transient ischemic attack, or intracranial hemorrhage.
    B) PHARMACOLOGY: Vorapaxar inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. Vorapaxar reversibly inhibits protease-activated receptor-1 (PAR-1), although its long half-life makes it effectively irreversible. Vorapaxar does not appear to affect coagulation parameters, nor does it inhibit platelet aggregation due to adenosine diphosphate, collagen, or thromboxane mimetic activities.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effect reported is bleeding, including life-threatening and fatal bleeding.
    2) INFREQUENT: Adverse effects that were reported less frequently include anemia, depression, dermatological reactions (ie, rashes, eruptions, and exanthemas), iron deficiency, retinopathy, and diplopia and other oculomotor disturbances.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, overdose has not been reported. It is anticipated that overdose effects are an extension of adverse effects observed with therapeutic doses.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) RETINOPATHY: According to 2 pooled placebo-controlled clinical studies, the incidence of retinopathy or retinal disorder was reported at a rate less than 2% of patients taking vorapaxar (n=19,632), but at a rate that was at least 40% greater than the patients receiving placebo (n=19,607) (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    2) DIPLOPIA: According to 2 pooled placebo-controlled clinical studies, diplopia and associated oculomotor disturbances occurred in 0.2% of patients taking vorapaxar (n=19,632) compared to 0.06% of patients receiving placebo (n=19,607) (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) INTRACRANIAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) According to a phase 3 placebo-controlled randomized clinical trial involving post-myocardial infarction or peripheral arterial disease patients without a history of stroke or transient ischemic attack, intracranial hemorrhage occurred in 0.4% of patients taking vorapaxar (n=10,059) compared to 0.3% of patients receiving placebo (n=10,049) (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    1) In this same study, involving post-myocardial infarction or peripheral arterial disease patients, who had a history of stroke, intracranial hemorrhage occurred in 2.4% of vorapaxar-treated patients (n=2870) compared to 0.9% of patients receiving placebo (n=2876) (p<0.001). Based on these results, the study, involving patients with a history of stroke, was terminated early, but was continued with patients who had no history of stroke. All percentages are calculated as Kaplan-Meier event rates at 3 years (Morrow et al, 2012).
    b) According to a double-blind randomized placebo-controlled trial, involving 12,887 patients who had acute coronary syndromes without ST-segment elevation, the incidence of intracranial hemorrhage was 1.1% in vorapaxar-treated patients (n=6446) compared to 0.2% in patients receiving placebo (n=6441) (p<0.001). Following an unscheduled safety review, patient follow-up in the trial was terminated early, with a median follow-up period of 502 days (range, 349 to 667 days) (Tricoci et al, 2012). All percentages are calculated as Kaplan-Meier event rates at 2 years.
    c) PREDISPOSING CONDITIONS: The risk of intracranial hemorrhage is increased in patients with a history of stroke, transient ischemic attacks, or intracranial hemorrhage; vorapaxar is contraindicated in these patient populations (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) According to a phase 3 placebo-controlled randomized clinical trial involving post-myocardial infarction or peripheral arterial disease patients without a history of stroke or transient ischemic attack, gastrointestinal bleeding occurred in 4% of patients taking vorapaxar (n=10,059) compared to 3% of patients receiving placebo (n=10,049) (Prod Info ZONTIVITY(TM) oral tablets, 2014)

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLEEDING
    1) WITH THERAPEUTIC USE
    a) According to a phase 3 placebo-controlled randomized clinical trial involving post-myocardial infarction or peripheral arterial disease patients without a history of stroke or transient ischemic attack, non-CABG-related mild, moderate, or severe bleeding occurred in 25% of patients taking vorapaxar (n=10,059) compared to 17.6% of patients receiving placebo (n=10,049). In this study, GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate bleeding was defined as bleeding without hemodynamic compromise but requiring therapeutic intervention (ie, transfusion of whole blood or packed red blood cells). GUSTO severe bleeding was defined as fatal, intracranial, or bleeding with hemodynamic compromise and requiring therapeutic intervention (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    b) MODERATE OR SEVERE BLEEDING
    1) According to a phase 3 placebo-controlled randomized clinical trial involving post-myocardial infarction or peripheral arterial disease patients without a history of stroke or transient ischemic attack, non-CABG-related moderate or severe bleeding occurred in 3% of patients taking vorapaxar (n=10,059) compared to 2% of patients receiving placebo (n=10,049). In this study, GUSTO moderate bleeding was defined as bleeding without hemodynamic compromise but requiring therapeutic intervention (ie, transfusion of whole blood or packed red blood cells). GUSTO severe bleeding was defined as fatal, intracranial, or bleeding with hemodynamic compromise and requiring therapeutic intervention (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    a) In this same study, involving post-myocardial infarction or peripheral arterial disease patients who had a history of stroke, GUSTO moderate or severe bleeding occurred in 4.7% of vorapaxar-treated patients compared to 2.8% of patients receiving placebo (p<0.001). Clinically significant bleeding, as defined by Thrombolysis in Myocardial Infarction (TIMI) criteria, occurred in 15.2% of vorapaxar-treated patients compared to 10.8% of patients receiving placebo. All percentages are calculated as Kaplan-Meier event rates at 3 years (Morrow et al, 2012).
    2) According to a double-blind randomized placebo-controlled trial, involving 12,887 patients who had acute coronary syndromes without ST-segment elevation, the incidence of moderate or severe bleeding, as defined by GUSTO, was 7.2% in vorapaxar-treated patients (n=6446) compared to 5.2% in patients receiving placebo (n=6441) (p<0.001). Following an unscheduled safety review, patient follow-up in the trial was terminated early, with a median follow-up period of 502 days (range, 349 to 667 days)(Tricoci et al, 2012). All percentages are calculated as Kaplan-Meier event rates at 2 years.
    a) In the same study, TIMI clinically significant bleeding was reported in 20.2% of patients treated with vorapaxar (n=6446) compared to 14.6% of patients receiving placebo (n=6441) (Tricoci et al, 2012).
    c) SEVERE BLEEDING
    1) According to a phase 3 placebo-controlled randomized clinical trial involving post-myocardial infarction or peripheral arterial disease patients without a history of stroke or transient ischemic attack, non-CABG-related severe bleeding occurred in 1% of patients taking vorapaxar (n=10,059) compared to 0.8% of patients receiving placebo (n=10,049). In this study, GUSTO severe bleeding was defined as fatal, intracranial, or bleeding with hemodynamic compromise and requiring therapeutic intervention (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    2) According to a double-blind randomized placebo-controlled trial, involving 12,887 patients who had acute coronary syndromes without ST-segment elevation, the incidence of severe bleeding, as defined by GUSTO, was 2.9% in vorapaxar-treated patients (n=6446) compared to 1.6% in patients receiving placebo (n=6441) (p<0.001). Following an unscheduled safety review, patient follow-up in the trial was terminated early, with a median follow-up period of 502 days (range, 349 to 667 days) (Tricoci et al, 2012). All percentages are calculated as Kaplan-Meier event rates at 2 years.
    a) In the same study, major bleeding, according to TIMI criteria, was reported in 4% of patients treated with vorapaxar (n=6446) compared to 2.5% of patients receiving placebo (n=6441) (p<0.001). Non-CABG-related major bleeding was reported in 2.7% and 1.3% of patients treated with vorapaxar and placebo, respectively (p<0.001) (Tricoci et al, 2012).
    d) FATAL BLEEDING: According to a phase 3 placebo-controlled randomized clinical trial involving post-myocardial infarction or peripheral arterial disease patients without a history of stroke or transient ischemic attack, fatal bleeding occurred in 0.2% of patients taking vorapaxar (n=10,059) compared to 0.1% of patients receiving placebo (n=10,049) (Prod Info ZONTIVITY(TM) oral tablets, 2014)
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) According to 2 pooled placebo-controlled clinical studies, anemia occurred in 5% of patients taking vorapaxar (n=19,632) compared to 4% of patients receiving placebo (n=19,607) (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    b) According to 2 pooled placebo-controlled clinical studies, the incidence of iron deficiency was reported at a rate less than 2% of patients taking vorapaxar (n=19,632), but at a rate that was at least 40% greater than the patients receiving placebo (n=19,607) (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) According to 2 pooled placebo-controlled clinical studies, rashes, eruptions, and exanthemas occurred in 2.2% of patients taking vorapaxar (n=19,632) compared to 2% of patients receiving placebo (n=19,607) (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Vorapaxar is classified as FDA pregnancy category B. There have been no embryo/fetal toxicities, malformations, or maternal toxicities in rats and rabbits exposed to vorapaxar during gestation 56 times and 26 times, respectively, the human systemic exposure at the recommended human dose.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS, RABBITS: Animal studies indicated that vorapaxar has a low probability of increased adverse developmental outcomes above background. No embryofetal or maternal toxicity, or embryofetal malformations were observed in rats that received 56 times the human systemic exposure at the recommended human dose (RHD), or in rabbits who received 26 times the RHD (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Vorapaxar is classified as FDA pregnancy category B (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) RATS, RABBITS: A decrease in perinatal survival and body weight gain were seen in rat pups from birth to postnatal day 4 and decreased body weight gain during the overall pre-weaning period when given doses 67 times the human exposure at the recommended human dose (RHD). Neurobehavioral and sensory function effects were seen in both male and female pups on days 20 and 21 after birth, but not later in development (during postnatal days [PND] 60 and 61). Additionally, memory impairment was observed in female pups on PND 27 at 31 times the human exposure at the RHD. In a study of rabbits, doses up to 20 mg/kg (approximately 89 times higher than the RHD) given during the period from implantation through closure of the fetal hard palate (days 7 to 19 of gestation) had a No Adverse Effect Level (NOAEL) for maternal or fetal toxicity that was equal to or above the highest dose tested. However, the number of litters with malformations increased with this same dose (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether vorapaxar is excreted into human milk, and the effects on the nursing infant from exposure to the drug in milk have not been determined. Because of the potential for severe toxicity in a nursing infant, it is recommended that either nursing or the drug be discontinued (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) Vorapaxar is actively secreted in the milk of lactating rats (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) There was no fertility impairment in male or female rats administered vorapaxar doses up to 50 mg/kg/day (40 and 67 times, respectively, the human systemic exposure at the recommended human dose) (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) During 2-year carcinogenicity studies, there was no evidence of carcinogenicity in male and female rats administered vorapaxar orally at doses up to 30 mg/kg/day (9 and 29-fold, respectively, the human systemic exposure at the recommended human dose) or in male and female mice administered vorapaxar orally at doses up to 15 mg/kg/day (up to 30-fold the human exposure) (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Genotoxicity

    A) There was no mutagenicity with vorapaxar according to the Ames bacterial reverse mutation assay, nor was vorapaxar clastogenic in an in vitro human peripheral blood lymphocyte assay or following intraperitoneal administration in an in vivo mouse micronucleus assay (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CBC with differential and platelet count following an overdose.
    B) Monitor for clinical evidence of bleeding.
    C) Monitor serial hemoglobin and hematocrit in patients with suspected bleeding.
    D) Obtain a head CT in patients with suspected intracranial bleeding.
    E) Routine serum coagulation profiles are not clinically useful in determining vorapaxar effect or toxicity in overdose. However, they may be useful to determine baseline coagulation deficiencies from pre-existing disease and/or coagulopathy caused by co-ingestions.
    F) Serum vorapaxar concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with moderate or severe bleeding, requiring therapeutic intervention, should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom diagnosis is unclear. A hematology consult should also be considered.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    B) The duration of observation is unknown as vorapaxar has an effective half-life of 3 to 4 days and an apparent terminal elimination half-life of 8 days (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Monitoring

    A) Monitor CBC with differential and platelet count following an overdose.
    B) Monitor for clinical evidence of bleeding.
    C) Monitor serial hemoglobin and hematocrit in patients with suspected bleeding.
    D) Obtain a head CT in patients with suspected intracranial bleeding.
    E) Routine serum coagulation profiles are not clinically useful in determining vorapaxar effect or toxicity in overdose. However, they may be useful to determine baseline coagulation deficiencies from pre-existing disease and/or coagulopathy caused by co-ingestions.
    F) Serum vorapaxar concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF TOXICITY
    a) Treatment is symptomatic and supportive. There is no known treatment to reverse the antiplatelet effect of vorapaxar. Platelet transfusion is not expected to be beneficial. Monitor serial CBC with differential. Whole blood or packed red blood cell transfusions as needed for moderate or severe bleeding.
    B) MONITORING OF PATIENT
    1) Monitor CBC with differential and platelet count following an overdose.
    2) Monitor for clinical evidence of bleeding.
    3) Monitor serial hemoglobin and hematocrit in patients with suspected bleeding.
    4) Obtain a head CT in patients with suspected intracranial bleeding.
    5) Routine serum coagulation profiles are not clinically useful in determining vorapaxar effect or toxicity in overdose. However, they may be useful to determine baseline coagulation deficiencies from pre-existing disease and/or coagulopathy caused by co-ingestions.
    6) Serum vorapaxar concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    C) BLEEDING
    1) Transfusion of whole blood or packed red cells may be needed in patients with moderate or severe bleeding.
    2) Transfusion of platelets is unlikely to be of value in managing bleeding (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding (99%) and large volume of distribution (424 liters) (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Range Of Toxicity

Summary

    A) TOXICITY: Toxic dose has not been established. Overdose has not been reported at the time of this review.
    B) THERAPEUTIC DOSE: ADULTS: The recommended dose is 2.08 mg orally once daily. CHILDREN: Safety and efficacy in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose is 2.08 mg orally once daily (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    B) Vorapaxar should be administered with aspirin and/or clopidogrel according their indications or standard of care. There is no experience with administration of vorapaxar as monotherapy and limited experience coadministered with other antiplatelet agents (Prod Info ZONTIVITY(TM) oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in pediatric patients have not been established (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Vorapaxar inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. Vorapaxar reversibly inhibits protease-activated receptor-1 (PAR-1), although its long half-life makes it effectively irreversible. Vorapaxar does not appear to affect coagulation parameters, nor does it inhibit platelet aggregation due to adenosine diphosphate, collagen, or a thromboxane mimetic activities. The effects of vorapaxar upon PAR-1 receptors found in tissues such as endothelial cells, neurons, and smooth muscle cells have not been assessed (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Physicochemical

Physical Characteristics

    A) Vorapaxar sulfate is a white to off-white solid that is freely soluble in methanol and slightly soluble in ethanol, acetone, 2-propanol, and acetonitrile. It is slightly soluble in pH 1 of aqueous solutions; however, its solubility decreases with increasing pH (Prod Info ZONTIVITY(TM) oral tablets, 2014).

Molecular Weight

    A) 590.7 (vorapaxar sulfate) (Prod Info ZONTIVITY(TM) oral tablets, 2014)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    3) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    4) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    5) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    6) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    7) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    8) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    9) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    10) Morrow DA, Braunwald E, Bonaca MP, et al: Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012; 366(15):1404-1413.
    11) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    12) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    13) Product Information: ZONTIVITY(TM) oral tablets, vorapaxar oral tablets. Merck & Co., Inc. (per manufacturer), Whitehouse Station, NJ, 2014.
    14) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    15) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    16) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    17) Tricoci P, Huang Z, Held C, et al: Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012; 366(1):20-33.