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TICAGRELOR AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ticareglor, a cyclo-pentyl-triazolo-pyrimidine, is an inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP-receptor used to reduce the rate of thrombotic cardiovascular events in patients with a history of acute coronary syndrome.

Specific Substances

    1) Ticgrelorum
    2) CAS 274693-27-5
    3) C23-H28-F2-N6-O4-S (Ticagrelor)
    4) Cangrelor
    5) C17-H21-N5-C12-F3-Na4-O12-P3-S2 (Cangrelor)
    1.2.1) MOLECULAR FORMULA
    1) CANGRELOR: C17H21N5C12F3Na4O12P3S2 (Prod Info KENGREAL(TM) intravenous injection, 2015)
    2) TICAGRELOR: C23H28F2N6O4S (Prod Info BRILINTA(R) oral tablets, 2015)

Available Forms Sources

    A) FORMS
    1) Ticagrelor is available as a 90 mg round, biconvex, yellow, film-coated tablet (Prod Info BRILINTA(TM) oral tablets, 2011)
    2) Cangarelor is available as a lyophilized powder in single use 10 mL (50 mg) vials (Prod Info KENGREAL(TM) intravenous injection, 2015).
    B) USES
    1) Ticagrelor is a P2Y12 platelet inhibitor used to reduce the rate of thrombotic cardiovascular events in patients with a history of acute coronary syndrome (including unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction) (Prod Info BRILINTA(TM) oral tablets, 2011).
    2) Cangrelor, a P2Y12 platelet inhibitor, is used as an adjunct to percutaneous coronary intervention for reducing the risk of periprocedural myocardial infarction, repeat coronary revascularization and stent thrombosis who have not been treated with a P2Y12 platelet inhibitor. It is administered via a dedicated infusion line, and once therapy is completed an oral P2Y12 platelet inhibitor should be continued (Prod Info KENGREAL(TM) intravenous injection, 2015).

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: Ticagrelor is used to reduce the rate of thrombotic cardiovascular events in patients with unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction. It is used in combination with aspirin. Cangrelor is a similar agent but is available for infusion only; once therapy is complete it should be followed by an oral P2Y(12) platelet inhibitor agent like ticagrelor.
    B) PHARMACOLOGY: Ticagrelor, a cyclo-pentyl-triazolo-pyrimidine, is orally active, selective and reversible inhibitor of platelet activation and aggregation mediated by the P2Y(12) ADP-receptor. It is also blocks ADP-mediated vasoconstriction of vascular smooth muscle and enhances the adenosine-induced coronary blood flow through inhibition of adenosine uptake by erythrocytes.
    C) EPIDEMIOLOGY: Limited data. Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The most common adverse events reported with therapeutic use are bleeding and dyspnea. Other events may include: chest pain, alterations in blood pressure, nausea, diarrhea, headache, dizziness, muscle pain and fatigue.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild to moderate bleeding and dyspnea may occur. Other events may include: bradycardia, nausea, diarrhea, chest pain, muscle pain, and fatigue.
    2) SEVERE TOXICITY: Major bleeding (eg, intracranial bleed, intrapericardial bleed with cardiac tamponade, hypovolemic shock or severe hypotension) or a decrease in hemoglobin of more than 5 g/dL may develop. Patients at greater risk to develop severe bleeding may include: older patients, those with a history of bleeding disorders, concomitant therapies (ie, anticoagulants, fibrinolytic therapy, higher doses of aspirin) or recent invasive procedures. Other symptoms may include: dyspnea, alterations in blood pressure and conduction abnormalities. An increase in serum creatinine levels may also develop.
    0.2.20) REPRODUCTIVE
    A) Ticagrelor and cangrelor are classified as FDA pregnancy category C. At the time of this review, there are no adequate and well controlled studies of ticagrelor use in pregnant women. In animal studies, structural abnormalities were observed at maternal doses about 5 to 7 times the maximum recommended human dose based on body surface area.
    0.2.21) CARCINOGENICITY
    A) CANGRELOR: At the time of this review, specific human carcinogenicity studies with cangrelor have not been conducted.

Laboratory Monitoring

    A) Monitor hematocrit, hemoglobin, partial thromboplastin time (PTT), platelet count, INR and fibrinogen in severe bleeding.
    B) Monitor vital signs, respiratory rate and effort. Obtain a baseline pulse oximetry level and monitor as indicated in patients with dyspnea. Obtain ABGs or chest x-ray in patients with persistent symptoms.
    C) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    D) Monitor renal function after a significant overdose.
    E) Monitor fluid and electrolyte status in patients with significant diarrhea.
    F) Serum ticagrelor 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 MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Dyspnea and bleeding are common adverse events. Monitor for evidence of bleeding. Transfusions of packed RBCs and other blood products may be needed. Monitor respiratory rate and effort; assess pulse oximetry. Administer oxygen as necessary. Obtain ABGs as indicated for persistent dyspnea. Replace fluids and electrolytes in patients with significant GI loss (ie, diarrhea, vomiting). Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Major bleeding may develop. Transfuse with RBCs, platelets and other blood products, as needed. Assess respiratory rate and effort, monitor pulse oximetry or ABGs. Administer oxygen as needed. Airway management may be indicated in patients that develop severe bleeding or hemodynamic instability. For severe toxicity, administer intravenous fluids and vasopressors for hypotension. Obtain a baseline ECG and institute continuous cardiac monitoring in symptomatic patients.
    C) DECONTAMINATION
    1) PREHOSPITAL: Emesis is not indicated. Consider activated charcoal in patients with a recent ingestion that are alert and able to protect their airway.
    2) HOSPITAL: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain their airway or if the airway is protected.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following a mild to moderate exposure. Patients with a severe exposure may develop severe bleeding and hemodynamic instability requiring airway support and mechanical ventilation.
    E) ANTIDOTE
    1) There is no known antidote.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be of value because ticagrelor is extensively protein bound (greater than 99%) and has an increased volume of distribution, and obtaining access for hemodialysis or hemoperfusion may induce bleeding complications.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic adult with an inadvertent minor exposure may be monitored at home. Due to limited experience, a child with more than a minor exposure (90 mg) should be observed in a healthcare center.
    2) OBSERVATION CRITERIA: Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients with dyspnea should be monitored until symptoms resolve and pulse oximetry and/or ABGs are normal. Patients with minor or minimal bleeding should be observed and discharged to home once bleeding has stopped and CBC and coagulation studies are within normal limits.
    3) ADMISSION CRITERIA: Patients with persistent dyspnea or evidence of severe bleeding should be admitted for further treatment.
    4) CONSULT CRITERIA: Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    H) PHARMACOKINETICS
    1) TICAGRELOR is extensively bound to plasma proteins (greater than 99%). It has a steady state volume of distribution of 88L. CYP3A4 is the major enzyme responsible for metabolism. Mean half-life is 7 to 12 hours for ticagrelor, and 9 hours for the active metabolite.
    2) CANGRELOR is extensively bound to plasma proteins (97% to 98%). Following an IV bolus, cangrelor reaches Cmax within 2 minutes. In healthy volunteers, a dose of 30 mcg/kg bolus plus 4 mcg/kg/min resulted in a volume of distribution of 3.9 L. Fifty eight percent of radioactivity was recovered in urine. The average elimination half-life is about 3 to 6 minutes.
    I) PITFALLS
    1) Discharged too early prior to hematologic or respiratory stability. Concomitant therapy that may increase bleeding risk (eg, aspirin therapy).
    J) DIFFERENTIAL DIAGNOSIS
    1) Other agents (ie, anticoagulant therapy, aspirin therapy, antiplatelet agents (ie, clopidogrel, prasugrel) or conditions that may cause an increase in bleeding tendencies.

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been determined for these agents. During clinical trials, doses above 180 mg daily were not studied.
    B) THERAPEUTIC USE: LOADING DOSE: 180 mg orally. MAINTENANCE THERAPY: ADULT: 90 mg orally twice daily along with a daily dose of aspirin (75 to 100 mg). PEDIATRIC: The safety and efficacy of ticagrelor in pediatric patients have not been established. CANGRELOR: ADULT: 30 mcg/kg IV bolus prior to percutaneous coronary intervention (PCI), then 4 mcg/kg/min IV infusion for at least 2 hours or for the duration of PCI, whichever is longer. PEDIATRIC: The safety and efficacy of ticagrelor in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Ticagrelor is used to reduce the rate of thrombotic cardiovascular events in patients with unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction. It is used in combination with aspirin. Cangrelor is a similar agent but is available for infusion only; once therapy is complete it should be followed by an oral P2Y(12) platelet inhibitor agent like ticagrelor.
    B) PHARMACOLOGY: Ticagrelor, a cyclo-pentyl-triazolo-pyrimidine, is orally active, selective and reversible inhibitor of platelet activation and aggregation mediated by the P2Y(12) ADP-receptor. It is also blocks ADP-mediated vasoconstriction of vascular smooth muscle and enhances the adenosine-induced coronary blood flow through inhibition of adenosine uptake by erythrocytes.
    C) EPIDEMIOLOGY: Limited data. Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The most common adverse events reported with therapeutic use are bleeding and dyspnea. Other events may include: chest pain, alterations in blood pressure, nausea, diarrhea, headache, dizziness, muscle pain and fatigue.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild to moderate bleeding and dyspnea may occur. Other events may include: bradycardia, nausea, diarrhea, chest pain, muscle pain, and fatigue.
    2) SEVERE TOXICITY: Major bleeding (eg, intracranial bleed, intrapericardial bleed with cardiac tamponade, hypovolemic shock or severe hypotension) or a decrease in hemoglobin of more than 5 g/dL may develop. Patients at greater risk to develop severe bleeding may include: older patients, those with a history of bleeding disorders, concomitant therapies (ie, anticoagulants, fibrinolytic therapy, higher doses of aspirin) or recent invasive procedures. Other symptoms may include: dyspnea, alterations in blood pressure and conduction abnormalities. An increase in serum creatinine levels may also develop.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) An increased incidence of Holter-detected bradyarrhythmias, including ventricular pauses, have been observed in patients who received ticagrelor during clinical studies. In a subgroup analysis of a randomized, double-blind study of approximately 3000 acute coronary syndrome patients, ventricular pauses were reported in 6% of patients who received ticagrelor compared with 3.5% of patients who received clopidogrel in the acute phase. After 1 month, incidence decreased to 2.2% and 1.6%, respectively (Prod Info BRILINTA(TM) oral tablets, 2011).
    B) SYNCOPE
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind study of patients with acute coronary syndrome, syncope, presyncope, and loss of consciousness were reported in 1.7% of patients who received ticagrelor (n=9235) compared with 1.5% of patients who received clopidogrel (n=9186). Both were coadministered with aspirin and other standard therapy for 6 to 12 months (Prod Info BRILINTA(TM) oral tablets, 2011).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind study of patients with acute coronary syndrome, dyspnea (exertional, nocturnal, paroxysmal nocturnal, and at rest) was reported in 13.8% of patients who received ticagrelor (n=9235) compared with 7.8% of patients who received clopidogrel (n=9186). Both were coadministered with aspirin and other standard therapy for 6 to 12 months (Prod Info BRILINTA(TM) oral tablets, 2011).
    B) COUGH
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind study of patients with acute coronary syndrome, cough was reported in 4.9% of patients who received ticagrelor (n=9235) compared with 4.6% of patients who received clopidogrel (n=9186). Both were administered with aspirin and other standard therapy for 6 to 12 months (Prod Info BRILINTA(TM) oral tablets, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind study of patients with acute coronary syndrome, headache was reported in 6.5% of patients who received ticagrelor (n=9235) compared with 5.8% of patients who received clopidogrel (n=9186). Both were coadministered with aspirin and other standard therapy for 6 to 12 months (Prod Info BRILINTA(TM) oral tablets, 2011).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind study of patients with acute coronary syndrome, dizziness was reported in 4.5% of patients who received ticagrelor (n=9235) compared with 3.9% of patients who received clopidogrel (n=9186). Both were coadministered with aspirin and other standard therapy for 6 to 12 months (Prod Info BRILINTA(TM) oral tablets, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind study of patients with acute coronary syndrome, nausea was reported in 4.3% of patients who received ticagrelor (n=9235) compared with 3.8% of patients who received clopidogrel (n=9186). Both were coadministered with aspirin and other standard therapy for 6 to 12 months (Prod Info BRILINTA(TM) oral tablets, 2011).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind study of patients with acute coronary syndrome, diarrhea was reported in 3.7% of patients who received ticagrelor (n=9235) compared with 3.3% of patients who received clopidogrel (n=9186). Both were coadministered with aspirin and other standard therapy for 6 to 12 months (Prod Info BRILINTA(TM) oral tablets, 2011).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind study of patients with acute coronary syndrome, a greater than 50% increase in serum creatinine levels were reported in 7.4% of patients who received ticagrelor (n=9235) compared with 5.9% of patients who received clopidogrel (n=9186). Both were coadministered with aspirin and other standard therapy for 6 to 12 months. Creatinine levels generally did not progress, and often decreased, with continued treatment (Prod Info BRILINTA(TM) oral tablets, 2011).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLEEDING
    1) WITH THERAPEUTIC USE
    a) TICAGRELOR: In a randomized, double-blind study of patients with acute coronary syndrome, total major and minor bleeding events (not related to CABG) were reported in 8.7% of patients who received ticagrelor (n=9235) compared with 7% of patients who received clopidogrel (n=9186). Both were coadministered with aspirin and other standard therapy for 6 to 12 months (Prod Info BRILINTA(TM) oral tablets, 2011).
    b) CANGRELOR: The most common adverse reaction is bleeding (Prod Info KENGREAL(TM) intravenous injection, 2015).
    c) CLINICAL TRIALS/POOLED ANALYSIS: In three phase 3 trials of 25,107 enrolled patients, 36 (0.29%) overdosed cangrelor patients were identified. Of these patients 20 were overdosed with both the bolus and infusion, 5 were overdosed with only the bolus and the remaining 11 were overdosed with the infusion. Most patients (n=21) only received 2.5 times the recommended dose (36 to less than 70 mcg/kg), 1 patient received 2.9 times (86.5 mcg/kg) the recommended dose and 3 patients received about 10 times (300 mcg/kg) the recommended dose. In addition, of the 31 patients that received a cangrelor infusion overdose, most (n=30) did not receive a dose greater than 2.5 to 3 times (10 to less than 12 mcg/kg per min) the recommended dose. Bleeding events did not appear to be dose dependent. Only 1 patient developed significant bleeding that required a blood transfusion. Serious adverse events were not reported and there was no increase in bleeding complications (compared to controls) which may be attributable to the drugs short half-life (Angiolillo et al, 2015).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind study of patients with acute coronary syndrome, back pain was reported in 3.6% of patients who received ticagrelor (n=9235) compared with 3.3% of patients who received clopidogrel (n=9186). Both were coadministered with aspirin and other standard therapy for 6 to 12 months (Prod Info BRILINTA(TM) oral tablets, 2011).
    B) NON-CARDIAC CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind study of patients with acute coronary syndrome, noncardiac chest pain was reported in 3.7% of patients who received ticagrelor (n=9235) compared with 3.3% of patients who received clopidogrel (n=9186). Both were coadministered with aspirin and other standard therapy for 6 to 12 months (Prod Info BRILINTA(TM) oral tablets, 2011).

Reproductive

    3.20.1) SUMMARY
    A) Ticagrelor and cangrelor are classified as FDA pregnancy category C. At the time of this review, there are no adequate and well controlled studies of ticagrelor use in pregnant women. In animal studies, structural abnormalities were observed at maternal doses about 5 to 7 times the maximum recommended human dose based on body surface area.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) TICAGRELOR: In animal studies, structural abnormalities were reported at maternal ticagrelor doses that were approximately 5 to 7 times the maximum recommended human dose (MRHD) on a mg/m(2) basis. Supernumerary liver lobes and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae were reported in the offspring of pregnant rats administered ticagrelor 300 mg/kg/day (16.5 times the MRHD on a mg/m(2) basis) during organogenesis. Delayed gallbladder development and incomplete ossification of the hyoid, pubis, and sternebrae in the fetus were reported when pregnant rabbits were administered ticagrelor 63 mg/kg/day (6.8 times the MRHD on a mg/m(2) basis) during organogenesis (Prod Info BRILINTA(TM) oral tablets, 2011).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Ticagrelor and cangrelor are classified as FDA pregnancy category C (Prod Info KENGREAL(TM) intravenous injection, 2015; Prod Info BRILINTA(TM) oral tablets, 2011).
    B) EMBRYO/FETAL RISK
    1) CANGRELOR
    a) Increased incidences of abortion and intrauterine losses were reported in animals administered cangrelor at doses approximately 12 times higher than the recommended human dose (Prod Info KENGREAL(TM) intravenous injection, 2015).
    C) ANIMAL STUDIES
    1) CANGRELOR: There were no reports of malformations or teratogenicity in animals administered cangrelor during reproduction studies. During animal embryofetal development studies, fetal growth retardation, characterized by incomplete ossification and unossified hind limb metatarsals, was reported with cangrelor doses approximately 5 times lower than the recommended human dose dose (Prod Info KENGREAL(TM) intravenous injection, 2015).
    2) TICAGRELOR: In a prenatal/postnatal study, pregnant rats were administered doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth occurred with doses of 180 mg/kg/day (approximately 10 times the maximum recommended human dose (MRHD) on a mg/m(2) basis) and delays in pinna unfolding and eye opening occurred with doses of 10 and 60 mg/kg/day (approximately 0.5 and 3.2 times the MRHD on a mg/m(2) basis) (Prod Info BRILINTA(TM) oral tablets, 2011).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) CANGRELOR: It is unknown whether cangrelor is excreted in breast milk. Exercise caution when administering cangrelor to a lactating woman (Prod Info KENGREAL(TM) intravenous injection, 2015).
    2) TICAGRELOR: It is unknown whether ticagrelor or its active metabolite are excreted in human milk (Prod Info BRILINTA(TM) oral tablets, 2011).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) CANGRELOR: There were no significant effects on male or female fertility in animals administered cangrelor at doses equal to the recommended human dose for 28 days (Prod Info KENGREAL(TM) intravenous injection, 2015).
    2) TICAGRELOR: Ticagrelor had no effect on male fertility at doses up to 180 mg/kg/day or on female fertility at doses up to 200 mg/kg/day. Doses of greater than or equal to 10 mg/kg/day to female rats produced an increased incidence of irregular duration of estrus cycles (Prod Info BRILINTA(TM) oral tablets, 2011).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) CANGRELOR: At the time of this review, specific human carcinogenicity studies with cangrelor have not been conducted.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) CANGRELOR: At the time of this review, specific human carcinogenicity studies with cangrelor have not been conducted (Prod Info KENGREAL(TM) intravenous injection, 2015).
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) CANGRELOR: At the time of this review, carcinogenicity studies with cangrelor have not been conducted (Prod Info KENGREAL(TM) intravenous injection, 2015).
    B) UTERINE CARCINOMAS
    1) TICAGRELOR: Uterine carcinomas, uterine adenocarcinomas and hepatocellular adenomas were observed in female rats at doses of 180 mg/kg/day (29-fold the maximally recommended dose of 90 mg twice daily on the basis of AUC). Ticagrelor was not carcinogenic in female rats receiving doses of 60 mg/kg/day (8-fold the maximum recommended human dose based on AUC) (Prod Info BRILINTA(TM) oral tablets, 2011).
    C) LACK OF EFFECT
    1) TICAGRELOR: Ticagrelor was not found to be carcinogenic in mice at doses up to 250 mg/kg/day or in male rats at doses up to 120 mg/kg/day (19 and 15 times the maximum recommended human dose of 90 mg twice daily on the basis of AUC, respectively) (Prod Info BRILINTA(TM) oral tablets, 2011).

Genotoxicity

    A) CANGRELOR: There was no evidence of genotoxicity, clastogenicity, or mutagenicity in the following tests: in vitro bacterial gene mutation assay, mouse lymphoma thymidine kinase assay, chromosome aberration assay in human peripheral lymphocytes, and in vivo bone marrow micronucleus assay in mice (Prod Info KENGREAL(TM) intravenous injection, 2015).
    B) TICAGRELOR: Ticagrelor was not genotoxic in the Ames bacterial mutagenicity test, mouse lymphoma assay and the rat micronucleus test, and the active O-demethylated metabolite was also not found to be genotoxic in the Ames assay or the mouse lymphoma assay (Prod Info BRILINTA(TM) oral tablets, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor hematocrit, hemoglobin, partial thromboplastin time (PTT), platelet count, INR and fibrinogen in severe bleeding.
    B) Monitor vital signs, respiratory rate and effort. Obtain a baseline pulse oximetry level and monitor as indicated in patients with dyspnea. Obtain ABGs or chest x-ray in patients with persistent symptoms.
    C) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    D) Monitor renal function after a significant overdose.
    E) Monitor fluid and electrolyte status in patients with significant diarrhea.
    F) Serum ticagrelor concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    4.1.2) SERUM/BLOOD
    A) Monitor hematocrit, hemoglobin, partial thromboplastin time (PTT), platelet count, INR and fibrinogen in severe bleeding.
    B) Monitor vital signs, respiratory rate and effort. Obtain a baseline pulse oximetry level and monitor as indicated in patients with dyspnea. Obtain ABGs or chest x-ray in patients with persistent symptoms.
    C) Monitor renal function after a significant overdose.
    D) Monitor fluid and electrolyte status in patients with significant diarrhea.
    E) Serum ticagrelor concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of dysrhythmias, or obtain an ECG in a patient with complaints of chest pain or syncope (Prod Info BRILINTA(TM) oral tablets, 2011).
    2) CHEST RADIOGRAPH
    a) Obtain a chest X-ray in patients with persistent dyspnea or respiratory symptoms. Dyspnea has commonly been reported with therapy (Prod Info BRILINTA(TM) oral tablets, 2011).
    3) MONITORING
    a) Monitor vital signs.

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 persistent dyspnea or evidence of severe bleeding should be admitted for further treatment.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic adult with an inadvertent minor exposure may be monitored at home. Due to limited experience, a child with more than a minor exposure (90 mg) should be observed in a healthcare center.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) A patient with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients with dyspnea should be monitored until symptoms resolve and pulse oximetry and/or ABGs are normal. Patients with minor or minimal bleeding should be observed and discharged to home once bleeding has stopped and CBC and coagulation studies are within normal limits.

Monitoring

    A) Monitor hematocrit, hemoglobin, partial thromboplastin time (PTT), platelet count, INR and fibrinogen in severe bleeding.
    B) Monitor vital signs, respiratory rate and effort. Obtain a baseline pulse oximetry level and monitor as indicated in patients with dyspnea. Obtain ABGs or chest x-ray in patients with persistent symptoms.
    C) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    D) Monitor renal function after a significant overdose.
    E) Monitor fluid and electrolyte status in patients with significant diarrhea.
    F) Serum ticagrelor 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) EMESIS/NOT RECOMMENDED
    1) Emesis is not recommended because of the risk of bleeding with repeated emesis.
    B) 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) Treatment is symptomatic and supportive. Dyspnea and bleeding are common adverse events. Monitor for evidence of bleeding. Transfusions of packed RBCs and other blood products may be needed. Monitor respiratory rate and effort; assess pulse oximetry. Administer oxygen as necessary. Obtain ABGs as indicated for persistent dyspnea. Replace fluids and electrolytes in patients with significant GI loss (ie, diarrhea, vomiting). Manage mild hypotension with IV fluids.
    B) MONITORING OF PATIENT
    1) Monitor hematocrit, hemoglobin, partial thromboplastin time (PTT), platelet count, INR and fibrinogen in severe bleeding.
    2) Monitor vital signs, respiratory rate and effort. Obtain a baseline pulse oximetry level and monitor as indicated in patients with dyspnea. Obtain ABGs or chest x-ray in patients with persistent symptoms.
    3) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    4) Monitor renal function after a significant overdose.
    5) Monitor fluid and electrolyte status in patients with significant diarrhea.
    6) Serum ticagrelor concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis is unlikely to be of value because ticagrelor is extensively protein bound (greater than 99%) and has an increased volume of distribution, and obtaining access for hemodialysis or hemoperfusion may induce bleeding complications.

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been determined for these agents. During clinical trials, doses above 180 mg daily were not studied.
    B) THERAPEUTIC USE: LOADING DOSE: 180 mg orally. MAINTENANCE THERAPY: ADULT: 90 mg orally twice daily along with a daily dose of aspirin (75 to 100 mg). PEDIATRIC: The safety and efficacy of ticagrelor in pediatric patients have not been established. CANGRELOR: ADULT: 30 mcg/kg IV bolus prior to percutaneous coronary intervention (PCI), then 4 mcg/kg/min IV infusion for at least 2 hours or for the duration of PCI, whichever is longer. PEDIATRIC: The safety and efficacy of ticagrelor in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) CANGRELOR: 30 mcg/kg IV bolus prior to percutaneous coronary intervention (PCI), then 4 mcg/kg/min IV infusion for at least 2 hours or for the duration of PCI, whichever is longer (Prod Info KENGREAL(TM) intravenous injection, 2015).
    B) TICAGRELOR: LOADING DOSE: 180 mg orally. MAINTENANCE THERAPY: Continue treatment with 90 mg twice daily. Patients are also receiving daily aspirin therapy (loading dose: 325 mg followed by a maintenance dose of 75 to 100 mg daily) (Prod Info BRILINTA(R) oral tablets, 2013).
    7.2.2) PEDIATRIC
    A) CANGRELOR: The safety and efficacy have not been established in pediatric patients (Prod Info KENGREAL(TM) intravenous injection, 2015).
    B) TICAGRELOR: The safety and efficacy of ticagrelor in pediatric patients have not been established (Prod Info BRILINTA(TM) oral tablets, 2011).

Minimum Lethal Exposure

    A) A minimum lethal dose has not been established for these agents (Prod Info BRILINTA(TM) oral tablets, 2011; Prod Info KENGREAL(TM) intravenous injection, 2015).

Maximum Tolerated Exposure

    A) SUMMARY
    1) TICAGRELOR: A maximum tolerated dose has not been established. Recommended therapy is 180 mg daily; higher doses were not studied during clinical trials (Prod Info BRILINTA(TM) oral tablets, 2011).
    2) CANGRELOR: In clinical trials, 36 patients received an overdose ranging from 36 to 300 mcg/kg (bolus dose) with no clinical sequelae observed (Prod Info KENGREAL(TM) intravenous injection, 2015).
    B) CANGRELOR
    1) CLINICAL TRIALS/POOLED ANALYSIS: In three phase 3 trials of 25,107 enrolled patients, 36 (0.29%) overdosed cangrelor patients were identified. Of these patients 20 were overdosed with both the bolus and infusion, 5 were overdosed with only the bolus and the remaining 11 were overdosed with the infusion. Most patients (n=21) only received 2.5 times the recommended dose (36 to less than 70 mcg/kg), 1 patient received 2.9 times (86.5 mcg/kg) the recommended dose and 3 patients received about 10 times (300 mcg/kg) the recommended dose. In addition, of the 31 patients that received a cangrelor infusion overdose, most (n=30) did not receive a dose greater than 2.5 to 3 times (10 to less than 12 mcg/kg per min) the recommended dose. Bleeding events did not appear to be dose dependent. Only 1 patient developed significant bleeding that required a blood transfusion. Serious adverse events were not reported and there was no increase in bleeding complications (compared to controls) which may be attributable to the drugs short half-life (Angiolillo et al, 2015).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) CANGRELOR: Following an IV bolus, cangrelor reaches Cmax within 2 minutes (Prod Info KENGREAL(TM) intravenous injection, 2015).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) TICAGRELOR
    1) Ticagrelor and its metabolite reversibly interacts with the platelet P2Y(12) ADP-receptor to prevent signal transduction and platelet activation (Prod Info BRILINTA(TM) oral tablets, 2011). It is a cyclo-pentyl-triazolo-pyrimidine, orally active, selective and reversible inhibitor of platelet activation and aggregation mediated by the P2Y(12) ADP-receptor. Ticagrelor is also able to block ADP-mediated vasoconstriction of vascular smooth muscle and enhance the adenosine-induced coronary blood flow through inhibition of adenosine uptake by erythrocytes. It differs from clopidogrel or prasugrel because it does not require hepatic biotransformation and can bind directly to the P2Y12 receptor (Tan et al, 2011).
    B) CANGRELOR
    1) Cangrelor is a direct P2Y(12) platelet receptor inhibit that can block ADP-induced platelet activation and aggregation (Prod Info KENGREAL(TM) intravenous injection, 2015).

Toxicologic Mechanism

    A) Bleeding should be anticipated following a significant exposure to ticagrelor or cangrelor (Tan et al, 2011; Prod Info KENGREAL(TM) intravenous injection, 2015). Based on overall comparisons with clopidogrel, ticagrelor demonstrated similar rates of total major bleeding, but it produced a higher incidence of non-CABG related bleeding (ie, several instances of fatal intracranial hemorrhage) (Tan et al, 2011). Patients receiving ticagrelor are also likely to develop dyspnea and bradyarrhythmias, which may be observed in overdose.

Physicochemical

Physical Characteristics

    A) CANGRELOR: A white to off-white lyophilized powder (Prod Info KENGREAL(TM) intravenous injection, 2015)
    B) TICAGRELOR: A crystalline powder (Prod Info BRILINTA(R) oral tablets, 2015)

Molecular Weight

    A) CANGRELOR: 864.3 g/mol (Prod Info KENGREAL(TM) intravenous injection, 2015)
    B) TICAGRELOR: 522.57 g/mol (Prod Info BRILINTA(R) oral tablets, 2015)

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) Angiolillo DJ, Bhatt DL, Steg PG, et al: Impact of cangrelor overdosing on bleeding complications in patients undergoing percutaneous coronary intervention: insights from the CHAMPION trials. J Thromb Thrombolysis 2015; 40(3):317-322.
    3) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    4) 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.
    5) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    6) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    7) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    8) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    9) 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.
    10) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    11) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    12) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    13) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    14) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    15) Product Information: BRILINTA(R) oral tablets, ticagrelor oral tablets. AstraZeneca LP (per FDA), Wilmington, DE, 2013.
    16) Product Information: BRILINTA(R) oral tablets, ticagrelor oral tablets. AstraZeneca LP (per manufacturer), Wilmington, DE, 2015.
    17) Product Information: BRILINTA(TM) oral tablets, ticagrelor oral tablets. AstraZeneca LP (per manufacturer), Wilmington, DE, 2011.
    18) Product Information: KENGREAL(TM) intravenous injection, cangrelor intravenous injection. The Medicines Company (per FDA), Parsippany, NJ, 2015.
    19) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    20) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    21) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    22) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    23) Tan GM, Lam YY, & Yan BP: Novel Platelet ADP P2Y12 Inhibitors in the Treatment of Acute Coronary Syndrome. Cardiovasc Ther 2011; Epub:Epub.
    24) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.