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General Risk of Bleeding
Drugs that inhibit platelet function including BRILINTA increase the risk of bleeding. BRILINTA 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 BRILINTA 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.
Concomitant Aspirin Maintenance Dose
In PLATO, use of BRILINTA with maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Therefore, after the initial loading dose of aspirin (usually 325 mg), use BRILINTA with a maintenance dose of aspirin of 75-100 mg [see DOSAGE AND ADMINISTRATION and Clinical Studies].
Moderate Hepatic Impairment
BRILINTA 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.
In PLATO, dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment, but occasionally required discontinuation (0.9% of patients taking BRILINTA versus 0.1% of patients taking clopidogrel). If a patient develops new, prolonged, or worsened dyspnea during treatment with BRILINTA, exclude underlying diseases that may require treatment. If dyspnea is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption. In the case of intolerable dyspnea requiring discontinuation of Brilinta, consider prescribing another antiplatelet agent.
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 BRILINTA
Avoid interruption of BRILINTA treatment. If BRILINTA must be temporarily discontinued (e.g., to treat bleeding or for elective surgery), restart it as soon as possible. Discontinuation of BRILINTA 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 DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Cytochrome CYP3A Potent Inducers
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide)
Benefits and Risks
- Tell patients to take BRILINTA exactly as prescribed.
- Inform patients not to discontinue BRILINTA without discussing it with the prescribing physician.
- Tell patients daily doses of aspirin should not exceed 100 mg and to avoid taking any other medications that contain aspirin.
- Tell patients to read the Medication Guide.
Inform patients that they:
- Will bleed and bruise more easily
- Will take longer than usual to stop bleeding
- Should report any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine.
Other Signs and Symptoms Requiring Medical Attention
- Inform patients that BRILINTA can cause shortness of breath. Tell them to contact their doctor if they experience unexpected shortness of breath, especially if severe.
Instruct patients to:
- Inform physicians and dentists that they are taking BRILINTA before any surgery or dental procedure.
- Tell the doctor performing any surgery or dental procedure to talk to the prescribing physician before stopping BRILINTA.
Tell patients to list all prescription medications, over-the-counter medications or dietary supplements they are taking or plan to take so the physician knows about other treatments that may affect bleeding risk (e.g. warfarin, heparin).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Ticagrelor was not carcinogenic in the mouse at doses up to 250 mg/kg/day or in the male rat at doses up to 120 mg/kg/day (19 and 15 times the MRHD of 90 mg twice daily on the basis of AUC, respectively). Uterine carcinomas, uterine adenocarcinomas and hepatocellular adenomas were seen 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), whereas 60 mg/kg/day (8-fold the MRHD based on AUC) was not carcinogenic in female rats.
Ticagrelor did not demonstrate genotoxicity when tested in the Ames bacterial mutagenicity test, mouse lymphoma assay and the rat micronucleus test. The active O-demethylated metabolite did not demonstrate genotoxicity in the Ames assay and mouse lymphoma assay.
Impairment of Fertility
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 ( > 15-fold the MRHD on the basis of AUC). Doses of ≥ 10 mg/kg/day given to female rats caused an increased incidence of irregular duration estrus cycles (1.5-fold the MRHD based on AUC).
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of BRILINTA use in pregnant women. In animal studies, ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. BRILINTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. The lowest dose was approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m² basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m² basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m² basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis and sternebrae occurred.
In a prenatal/postnatal study, pregnant rats received ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m² basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m² basis).
It is not known whether ticagrelor or its active metabolites are excreted in human milk. Ticagrelor is excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from BRILINTA, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of BRILINTA in pediatric patients have not been established.
In PLATO, 43% of patients were ≥ 65 years of age and 15% were ≥ 75 years of age. The relative risk of bleeding was similar in both treatment and age groups.
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.
BRILINTA has not been studied in the patients with moderate or severe hepatic impairment. Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Hence, BRILINTA 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, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 4/15/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Brilinta Information
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