Ticagrelor

Ticagrelor

Clinical data
Routes of administration	oral
ATC code	none
Pharmacokinetic data
Bioavailability	36%
Protein binding	99%
Metabolism	hepatic (CYP3A4)
Elimination half-life	6.9 h
Excretion	mainly biliary
Identifiers
IUPAC name (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol
CAS Number	274693-27-5
PubChem CID	9871419
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C23H28F2N6O4S
Molar mass	522.567 g/mol
3D model (JSmol)	Interactive image
SMILES Fc2ccc(cc2F)C3CC3Nc5nc(SCCC)nc4c5nnn4C1CC(C(O)C1O)OCCO

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Synonyms and keywords: Brilinta

To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or the FDA Medwatch site.

Overview

Ticagrelor (previously known as AZD6140) is a member of a new generation of P2Y₁₂ inhibitors. Chemically, this is a first-in-class member of the cyclo-pentyl-triazolo-pyrimidine (CPTP) family with a mean terminal half-life of approximately 7 h and a median Tmax of 2.6 h. Ticagrelor’s steady-state volume of distribution (87.5 L) indicates it does not extensively distribute into or bind to tissues.

Indications

Ticagrelor is a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction). Ticagelor has been shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction, or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis.

Ticagrelor has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of Ticagrelor. Avoid maintenance doses of aspirin above 100 mg daily.

Method of action

Like thienopyridines, ticagrelor is only orally available, but in contrast with these pro-drugs, ticagrelor is direct acting, i.e. does not require metabolic activation. In addition, ticagrelor is a reversible P2Y₁₂ inhibitor with more rapid onset and off set of action compared with clopidogrel. Ticagrelor has 2 metabolites. The major ticagrelor metabolite (AR-C124910XX) has a P2Y₁₂ inhibiting activity comparable to the parent compound while a second metabolite (AR-C133913XX) is inactive. Ticagrelor is rapidly and extensively metabolized in the liver by CYP3A4. The P2Y₁₂ receptor is targeted by ticagrelor via a mechanism that is non-competitive with ADP, suggesting the existence of an independent receptor-binding site. Compared with clopidogrel, ticagrelor provides greater and more consistent platelet inhibition.

Dosing

Initiate Ticagrelor treatment with a 180 mg (two 90 mg tablets) loading dose and continue treatment with 90 mg twice daily After the initial loading dose of aspirin (usually 325 mg), use Ticagrelor with a daily maintenance dose of aspirin of 75-100 mg.

ACS patients who have received a loading dose of clopidogrel may be started on Ticagrelor.

Ticagrelor can be administered with or without food.

A patient who misses a dose of Ticagrelor should take one 90 mg tablet (their next dose) at its scheduled time.

Dosage Forms and Strengths

Ticagrelor 90 mg is supplied as a round, biconvex, yellow, film-coated tablet marked with a “90” above “T” on one side.

Contraindications

History of Intracranial Hemorrhage

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

Active Bleeding

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

Severe Hepatic Impairment

Ticagrelor is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure, and it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins.

Warnings and Precautions

General Risk of Bleeding

Drugs that inhibit platelet function including Ticagrelor increase the risk of bleeding. Ticagrelor increased the overall risk of bleeding (Major + Minor) to a somewhat greater extent than did clopidogrel. The increase was seen for non-CABG-related bleeding, but not for CABG-related bleeding. Fatal and life-threatening bleeding rates were not increased.

In general, risk factors for bleeding include older age, a history of bleeding disorders, performance of percutaneous invasive procedures, and concomitant use of medications that increase the risk of bleeding (e.g., anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal anti-inflammatory drugs [NSAIDS]).

When possible, discontinue Ticagrelor five days prior to surgery. Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures, even if the patient does not have any signs of bleeding.

If possible, manage bleeding without discontinuing Ticagrelor. Stopping Ticagrelor increases the risk of subsequent cardiovascular events.

Concomitant Aspirin Maintenance Dose

In PLATO, use of Ticagrelor with maintenance doses of aspirin above 100 mg decreased the effectiveness of Ticagrelor. Therefore, after the initial loading dose of aspirin (usually 325 mg), use Ticagrelor with a maintenance dose of aspirin of 75-100 mg.

Moderate Hepatic Impairment

Ticagrelor has not been studied in patients with moderate hepatic impairment. Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.

Dyspnea

Dyspnea was reported in 14% of patients treated with Ticagrelor and in 8% of patients taking clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment. If a patient develops new, prolonged, or worsened dyspnea during treatment with Ticagrelor, exclude underlying diseases that may require treatment. If dyspnea is determined to be related to Ticagrelor, no specific treatment is required; continue Ticagrelor without interruption.

In a substudy, 199 patients from PLATO underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no significant difference between treatment groups for FEV1. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment.

Discontinuation of Ticagrelor

Avoid interruption of Ticagrelor treatment. If Ticagrelor must be temporarily discontinued (e.g., to treat bleeding or for elective surgery), restart it as soon as possible. Discontinuation of Ticagrelor will increase the risk of myocardial infarction, stent thrombosis, and death.

Strong Inhibitors of Cytochrome CYP3A

Ticagrelor is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole.

Cytochrome CYP3A Potent Inducers

Avoid use with potent CYP3A inducers, such as rifampin, dexamethasone, phenytoin, rbamazepine, and phenobarbital.

Sources

The content on this page relies heavily on copyleft content from the United States Food and Drug Administration product label.