Ticagrelor

Concomitant administration of ticagrelor and digoxin did not substantially affect pharmacokinetics of digoxin; therefore, these drugs may be used concomitantly without dosage adjustments. However, because of the possibility of increased digoxin concentrations as a result of P-glycoprotein inhibition, serum digoxin concentrations should be monitored during initiation of and following any change in ticagrelor therapy.

When ticagrelor is used in conjunction with aspirin maintenance dosages exceeding 100 mg daily, efficacy of ticagrelor may be reduced.

Ticagrelor is a substrate and weak inhibitor of the P-glycoprotein transport system. Increased serum concentrations of P-glycoprotein substrates (e.g., digoxin) are possible when these drugs are used concomitantly with ticagrelor; appropriate laboratory and/or clinical monitoring is recommended.

Concomitant administration of ticagrelor and rifampin 600 mg once daily substantially decreased peak plasma concentrations of and systemic exposure to ticagrelor. Concomitant use of ticagrelor and rifampin should therefore be avoided.

For more Interactions (Complete) data for Ticagrelor (9 total), please visit the HSDB record page.

In several large clinical trials, ticagrelor was not associated with serum enzyme elevations during therapy and no instances of clinically apparent liver injury were reported. While there have been isolated reports of transient and mild serum enzyme elevations during ticagrelor therapy, these have been short lived and asymptomatic. In addition, since marketing and release, there have been no reports of isolated clinically apparent liver injury or jaundice associated with ticagrelor therapy and hepatotoxicity is not mentioned in the product label. On the other hand, there have been several reports of jaundice and liver injury associated with rhabdomyolysis and with thrombotic thrombocytopenic purpura that represented secondary effects of these severe adverse events. Thus, significant liver injury due to ticagrelor occurs but has occurred largely in association with other life-threatening complications.；Likelihood score: D (possible rare cause of liver injury due to complications of severe allergic reactions or drug-drug interactions).

IDENTIFICATION AND USE: Ticagrelor is a crystalline powder. As the drug Brilinta, it is indicated to reduce the rate of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction (MI). Brilinta also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS. HUMAN EXPOSURE AND TOXICITY: Symptoms of overdose may include bleeding, gastrointestinal effects (nausea, vomiting and diarrhea) and ventricular pauses. Blood loss is the predominant risk. ANIMAL STUDIES: The acute toxicity of the drug is considered low. The results of single dose studies in mice and rats showed that ticagrelor was well tolerated when given orally by gavage at doses approximately 550 times the recommended human daily dose on a mg/kg basis. Repeat-dose studies were conducted in mice, rats and marmosets. Indications of subclinical bleeding were observed across species. Increased liver weight at high doses occurred in rodents. Ticagrelor had no effects on parturition or postnatal development in rats at doses up to 60 mg/kg/day (4.6 times the human therapeutic exposure), but did cause maternal and developmental toxicity in pups at 180 mg/kg. Ticagrelor given during the period of organogenesis had no effect on fetal development at oral doses up to 100 mg/kg/day in rats (5.1 times the human therapeutic exposure) and up to 42 mg/kg/day in rabbits (equivalent to the human therapeutic exposure). Ticagrelor and the active metabolite AR-C124910XX did not demonstrate any genotoxic potential in bacterial in vitro test, in vitro mouse lymphoma L5178Y TK+/- 3.7.2C cell, and in vivo rat bone marrow micronucleus assays.

/SIGNS AND SYMPTOMS/ Bleeding is the expected pharmacologic effect of overdosing. If bleeding occurs, appropriate supportive measures should be taken. Other effects of overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG.

/SIGNS AND SYMPTOMS/ Like other antiplatelet agents, ticagrelor increases the risk of bleeding, which may be serious and sometimes fatal.

/EPIDEMIOLOGY STUDIES/ /The purpose of this study was/ to evaluate the effect of Ticagrelor on intra- and postoperative bleeding complications in patients undergoing coronary bypass surgery. For this study, patients who underwent on-pump or off-pump coronary bypass surgery with preoperative acetylsalicylic acid (ASA) and Ticagrelor administration, between January 2014 and December 2014, were included. In the matched control group, continued dual antiplatelet therapy (DAPT) consisted of Clopidogrel and ASA. A total of 28 consecutive patients (24 males; 73 + or - 6.6 years) with preoperative Ticagrelor intake underwent elective (n = 22), urgent (n = 2) or emergency (n = 4) cardiac bypass surgery. The postoperative blood loss, red blood cell units given and intra- and postoperative bleeding complications were documented. To evaluate the effect of Ticagrelor treatment on bleeding during and after coronary bypass surgery in a non-randomized study, we used a case-matched analysis. Baseline parameters showed no important differences between the study group and the control group regarding the matching variables, left ventricular function, preoperative clinical status and risk stratification. The preoperative laboratory analysis showed no important differences regarding coagulation and blood cell count parameters. Overall blood loss was significantly higher in the study group with a mean loss of 1028.8 + or - 735.5 mL (P = 0.0002). Accordingly, units of red blood cells administered were also significantly higher in the study group (P = 0.0002). In the Ticagrelor group, there were six rethoracotomies due to postoperative bleeding with a blood loss of more than 1200 mL in the first 3 hr. With no rethoracotomies in the Clopidogrel group, this also showed statistical significance for the postoperative course (P = 0.02). There were no differences found regarding ICU stay and ventilation time. Comparing the mean hospital stay, the study group presented a significantly longer stay

/EPIDEMIOLOGY STUDIES/ Ticagrelor (Brilique) is a novel reversible platelet inhibitor at P2Y12 receptor used in patients with acute coronary syndrome and patients undergoing percutaneous coronary interventions. Unlike clopidogrel (Plavix), ticagrelor has a quicker offset of action, and therefore, it seems that platelet function recovers faster on discontinuation of therapy. These drugs sometimes cannot be stopped before coronary artery bypass grafting due to the risk of stent thrombosis or in case of emergency operations. Therefore, we investigated whether the continued preoperative use of ticagrelor influences the perioperative course of cardiac surgical patients. The perioperative course and clinical outcomes of patients preoperatively receiving ticagrelor + acetylsalicylic acid (ASA) (n = 32) or clopidogrel + ASA (n = 49) until cardiac surgery, performed at University of Goettingen between January 2012 and December 2012, were studied. The study was designed as a retrospective observational study. The observation period started with the surgery and ended after 3 days. P < 0.05 was considered statistically significant. Preoperative data and intraoperative characteristics were almost similar among the groups. In the first 24 hr, the median blood loss was 850 [780-1600] mL in the ticagrelor group and 680 [400-860] mL in the clopidogrel group (P = 0.0006). Furthermore, the median red blood cell transfusion (P = 0.0031), the median pooled platelet transfusion (P = 0.0012), the median prothrombin complex concentrate use (P = 0.0114) and the median fibrinogen use (P = 0.0118) were significantly higher in the ticagrelor group compared with the clopidogrel group. However, there was no statistical significance between the two groups regarding intensive care unit and hospital stay, mechanical ventilation time, incidence of acute kidney injury and mortality. Hence, a tendency towards more rethoracotomies due to bleeding in the ticagrelor group was observed (P = 0.0632). In c

Drug Induced Liver Injury Rank (DILIrank 2.0)

Ticagrelor

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ The acute toxicity of ticagrelor is considered low. The results of single dose studies in CD-1 mice and Sprague-Dawley rats showed that ticagrelor was well tolerated when given orally by gavage following doses up to 2000 mg/kg (the highest dose tested). This dose represents approximately 550 times the recommended human daily dose on a mg/kg basis.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Repeat-dose studies were conducted in mice, rats and marmosets. Consistent observations across species in repeat dose studies were seen primarily in the gastrointestinal tract, but were inconsistent with respect to the location, severity, and type of the observations. Indications of subclinical bleeding were also observed across species. Increased liver weight at high doses occurred in rodents. In rats, this was accompanied by centrilobular hypertrophy and induction of cytochrome P450 liver enzymes, and was reversible upon withdrawal of treatment. Adrenal weights increased at higher doses in the repeat dose studies in rodents, and were reversible upon withdrawal of treatment.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Ticagrelor had no effects on parturition or postnatal development in rats at doses up to 60 mg/kg/day (4.6 times the human therapeutic exposure), but did cause maternal (reduced body weight gain and food consumption) and developmental toxicity in pups (reduced post-natal viability, lower birth weight, and delayed growth and physical development) at 180 mg/kg.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Ticagrelor given during the period of organogenesis had no effect on fetal development at oral doses up to 100 mg/kg/day in rats (5.1 times the human therapeutic exposure) and up to 42 mg/kg/day in rabbits (equivalent to the human therapeutic exposure). Fetal effects that were considered to be developmental variants or delays were seen in fetuses from female rats given 300 mg/kg (decreased body weight, 27 pre-pelvic vertebral arches, extra 14th ribs, and incomplete ossification of various skeletal structures), that may have resulted from maternal toxicity, and fetal developmental delays were also seen in rabbits given 63 mg/kg (increased incidences of clear gall bladder contents, incompletely ossified hyoid and pubis, one or more incomplete ossification of various skeletal structures), at which there was no overt maternal toxicity.

For more Non-Human Toxicity Excerpts (Complete) data for Ticagrelor (8 total), please visit the HSDB record page.

Brilinta is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

Brilinta is contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population.

Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Avoid use of Brilinta in patients with severe hepatic impairment. There is limited experience with Brilinta in patients with moderate hepatic impairment; consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.

Ticagrelor is a direct-acting reversibly binding P2Y12 antagonist and is widely used as an antiplatelet therapy for the prevention of cardiovascular events in acute coronary syndrome patients. However, antiplatelet therapy can be associated with an increased risk of bleeding. Here, we present data on the identification and the in vitro and in vivo pharmacology of an antigen-binding fragment (Fab) antidote for ticagrelor. The Fab has a 20 pM affinity for ticagrelor, which is 100 times stronger than ticagrelor's affinity for its target, P2Y12. Despite ticagrelor's structural similarities to adenosine, the Fab is highly specific and does not bind to adenosine, adenosine triphosphate, adenosine 5'-diphosphate, or structurally related drugs. The antidote concentration-dependently neutralized the free fraction of ticagrelor and reversed its antiplatelet activity both in vitro in human platelet-rich plasma and in vivo in mice. Lastly, the antidote proved effective in normalizing ticagrelor-dependent bleeding in a mouse model of acute surgery. This specific antidote for ticagrelor may prove valuable as an agent for patients who require emergency procedures.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

◉ Summary of Use during Lactation；No published information is available on the use of ticagrelor during breastfeeding. Because ticagrelor and its active metabolite are more than 99% bound to plasma proteins, the amount in milk is likely to be low. However, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. If it is used by a nursing mother, monitor the infant for bruising and bleeding.；◉ Effects in Breastfed Infants；Relevant published information was not found as of the revision date.；◉ Effects on Lactation and Breastmilk；Relevant published information was not found as of the revision date.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ticagrelor, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

MEDICATION

Purinergic P2Y Receptor Antagonists