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 (see Adverse Reactions).
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 (see Warnings and Adverse Reactions).
Concomitant aspirin maintenance dose: 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 (see Dosage & Administration).
Dyspnea: 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. 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 (see Interactions).
Cytochrome CYP3A potent inducers: Avoid use with potent CYP3A inducers, such as rifampin, phenytoin, carbamazepine, and phenobarbital (see Interactions).
Surgery: Patients should be advised to inform physicians and dentists that they are taking ticagrelor before any surgery is scheduled and before any new medicinal product is taken. Patients undergoing coronary artery bypass grafting (CABG), ticagrelor had more bleeding than clopidogrel when stopped within 1 day prior to surgery but a similar rate of major bleeds compared to clopidogrel after stopping therapy 2 or more days before surgery. If a patient is to undergo elective surgery and antiplatelet effect is not desired, ticagrelor should be discontinued 7 days prior to surgery.
Patients with prior ischemic stroke: Acute coronary syndromes (ACS) patients with prior ischemic stroke can be treated with ticagrelor for up to 12 months. Patients with history of myocardial infarction (MI) with prior ischemic stroke were not included. Therefore, in the absence of data, treatment beyond one year is not recommended in these patients.
Patients at risk of bradycardia events: Due to the limited clinical experience, ticagrelor should be used with caution in these patients.
In addition, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia. However, no evidence of clinically significant adverse reactions was observed after concomitant administration with one or more medicinal products known to induce bradycardia (e.g., 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin).
Creatinine elevations: Creatinine levels may increase during treatment with ticagrelor. The mechanism has not been elucidated. Renal function should be checked according to routine medical practice. In patients with acute coronary syndromes (ACS), it is recommended that renal function is also checked one month after initiating the treatment with ticagrelor, paying special attention to patients ≥75 years, patients with moderate/severe renal impairment, and those receiving concomitant treatment with an angiotensin receptor blocker (ARB).
Uric acid increase: Hyperuricemia may occur during treatment with ticagrelor. Caution is advised in patients with history of hyperuricemia or gouty arthritis. As a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged.
Other: Coadministration of ticagrelor and high maintenance dose acetylsalicylic acid (>300 mg) is not recommended.
Premature discontinuation: Premature discontinuation with any antiplatelet therapy, including ticagrelor, could result in an increased risk of cardiovascular (CV) death or myocardial infarction (MI) due to the patient's underlying disease. Therefore, premature discontinuation of treatment should be avoided.
Hepatic impairment: Use of ticagrelor is contraindicated in patients with severe hepatic impairment.
There is limited experience with ticagrelor in patients with moderate hepatic impairment. Therefore, caution is advised in these patients. Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.
Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Hence, ticagrelor is contraindicated for use in patients with severe hepatic impairment and its use should be considered carefully in patients with moderate hepatic impairment. No dosage adjustment is needed in patients with mild hepatic impairment (see Contraindications).
Renal impairment: No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied.
Use in Pregnancy: Pregnancy category: C.
There are no adequate and well-controlled studies of ticagrelor use in pregnant women. Ticagrelor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in Lactation: It is not known whether ticagrelor or its active metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ticagrelor, a decision should be made whether to discontinue nursing or to discontinue drug.
Use in Children: The safety and effectiveness of ticagrelor in pediatric patients have not been established.
Use in Elderly: No overall differences in safety or effectiveness were observed between these patients and younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.