Ticagrelor
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2]
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Black Box Warning
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WARNING: (A) BLEEDING RISK, and (B) ASPIRIN DOSE AND Brilinta EFFECTIVENESS
See full prescribing information for complete Boxed Warning.
BLEEDING RISK:
Brilinta, like other antiplatelet agents, can cause significant, sometimes fatal bleeding. Do not use Brilinta in patients with active pathological bleeding or a history of intracranial hemorrhage. Do not start Brilinta in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue Brilinta at least 5 days prior to any surgery. Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgery. If possible, manage bleeding without discontinuing Brilinta. Stopping Brilinta increases the risk of subsequent cardiovascular events.
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Overview
Ticagrelor is a P2Y12 platelet inhibitor, Platelet aggregation inhibitor that is FDA approved for the {{{indicationType}}} of acute coronary syndromes (ACS) (unstbale angina), non-ST elevation myocardial infarction, or ST elevation myocardial infarction).. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Major and minor bleeding, headache, elevated serum creatinine, cough and dyspnea.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Acute coronary syndromes
- Dosing Information
- Initial dose: “Brilinta 180 mg PO once” with aspirin (325 mg) once.
- Maintenance dose: “Brilinta 90 mg PO bid” with aspirin 75-100 mg PO qd.
- Not recommended when aspirin maintenance dose is above 100 mg.
Percutaneous coronary intervention
- Dosing Information
- Loading dose: “Brilinta 180 mg PO” with aspirin (325 mg), once.
- Maintenance: “Brilinta 90 mg PO bid” with aspirin 75-100 mg qd.
- Use of aspirin maintenance dose above 100 mg is not recommended.
- Consider carefully the continuation of therapy beyond 12 months (for drug-eluting stents).
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information about Off-Label Use and Dosage of Ticagrelor tablet in adult patients.
Non–Guideline-Supported Use
There is limited information about Off-Label Use and Dosage of Ticagrelor tablet in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information about ‘’FDA-Labeled Indications and Dosage” of Ticagrelor tablet in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information about Off-Label Use and Dosage of Ticagrelor tablet in pediatric patients.
Non–Guideline-Supported Use
There is limited information about Off-Label Use and Dosage of Ticagrelor tablet in pediatric patients.
Contraindications
- History of intracranial hemorrhage
- Active pathological bleeding
- Severe hepatic impairment
- Hypersensitivity to ticagrelor or any component of the product
Warnings
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WARNING: (A) BLEEDING RISK, and (B) ASPIRIN DOSE AND Brilinta EFFECTIVENESS
See full prescribing information for complete Boxed Warning.
BLEEDING RISK:
Brilinta, like other antiplatelet agents, can cause significant, sometimes fatal bleeding. Do not use Brilinta in patients with active pathological bleeding or a history of intracranial hemorrhage. Do not start Brilinta in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue Brilinta at least 5 days prior to any surgery. Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgery. If possible, manage bleeding without discontinuing Brilinta. Stopping Brilinta increases the risk of subsequent cardiovascular events.
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- Like other antiplatelet agents, Brilinta increases the risk of bleeding.
- In PLATO, use of Brilinta with maintenance doses of aspirin above 100 mg decreased the effectiveness of Brilinta.
- Moderate Hepatic Impairment: Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.
- Dyspnea: Dyspnea was reported more frequently with Brilinta than with clopidogrel. Dyspnea resulting from Brilinta is self-limiting. Rule out other causes.
- Discontinuation of Brilinta: Premature discontinuation increases the risk of myocardial infarction, stent thrombosis, and death.
Adverse Reactions
Clinical Trials Experience
Clinical Trials Experience
The following adverse reactions are also discussed elsewhere in the labeling: Warnings
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Brilinta has been evaluated for safety in more than 10000 patients, including more than 3000 patients treated for more than 1 year.
Bleeding
PLATO used the following bleeding severity categorization:
- Major bleed – fatal/life-threatening. Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells (PRBCs)) for bleeding.
- Major bleed – other. Any one of the following: significantly disabling (e.g., intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2-3 units (whole blood or PRBCs) for bleeding.
- Minor bleed. Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing).
- Minimal bleed. All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or treatment.
Figure 1 shows major bleeding events over time. Many events are early, at a time of coronary angiography, PCI, CABG, and other procedures, but the risk persists during later use of antiplatelet therapy.
Figure 1- Kaplan-Meier estimate of time to first PLATO-defined ‘Total Major’ bleeding event
Annualized rates of bleeding are summarized in Table 1 below. About half of the bleeding events were in the first 30 days.
As shown in Table 1, Ticagrelor was associated with a somewhat greater risk of non- CABG bleeding than was Clopidogrel. No baseline demographic factor altered the relative risk of bleeding with Ticagrelor compared to Clopidogrel.
In PLATO, 1584 patients underwent CABG surgery. The percentages of those patients who bled are shown in Table 2. Rates were very high but similar for Ticagrelor and Clopidogrel.
Although the platelet inhibition effect of Ticagrelor has a faster offset than Clopidogrel in in vitro tests and Ticagrelor is a reversibly binding P2Y12 inhibitor, PLATO did not show an advantage of Ticagrelor compared to Clopidogrel for CABG-related bleeding. When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of Ticagrelor treated patients and 79% on Clopidogrel.
No data exist with Ticagrelor regarding a hemostatic benefit of platelet transfusions.
Drug Discontinuation
In PLATO, the rate of study drug discontinuation attributed to adverse reactions was 7.4% for Ticagrelor and 5.4% for clopidogrel. Bleeding caused permanent discontinuation of study drug in 2.3% of Ticagrelor patients and 1.0% of clopidogrel patients. Dyspnea led to study drug discontinuation in 0.9% of Ticagrelor and 0.1% of clopidogrel patients.
Common Adverse Events
A variety of non-hemorrhagic adverse events occurred in PLATO at rates of 3% or more. These are shown in Table 3. In the absence of a placebo control, whether these are drug related cannot be determined in most cases, except where they are more common on Ticagrelor or clearly related to the drug’s pharmacologic effect (dyspnea).
Bradycardia
In clinical studies Ticagrelor has been shown to increase the occurrence of Holter-detected bradyarrhythmias (including ventricular pauses). PLATO excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker). In PLATO, syncope, pre-syncope and loss of consciousness were reported by 1.7% and 1.5% of BRILINTA and clopidogrel patients, respectively.
In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with Ticagrelor (6.0%) than with Clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6% respectively after 1 month.
Gynecomastia In PLATO, gynecomastia was reported by 0.23% of men on BRILINTA and 0.05% on Clopidogrel. Other sex-hormonal adverse reactions, including sex organ malignancies, did not differ between the two treatment groups in PLATO.
Lab abnormalities
Serum Uric Acid:
Serum uric acid levels increased approximately 0.6 mg/dL from baseline on Ticagrelor and approximately 0.2 mg/dL on Clopidogrel in PLATO. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group).
Serum Creatinine:
In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving Ticagrelor compared to 5.9% of patients receiving Clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of BRILINTA. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune system disorders – Hypersensitivity reactions including angioedema. See Contraindications.
Drug Interactions
Effects of other drugs
Ticagrelor is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5. Ticagrelor is also a p-glycoprotein (P-gp) substrate.
CYP3A inhibitors
Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin). See Warnings and Pharmacology.
CYP3A inducers
Avoid use with potent inducers of CYP3A (e.g., rifampin, dexamethasone, phenytoin, carbamazepine and phenobarbital) See #Contraindications⎪Contraindications, Pharmacology and Warnings.
Aspirin
See Pharmacology and Warnings.
Effect of ticagrelor on other drugs.
Ticagrelor is an inhibitor of CYP3A4/5 and the P-glycoprotein transporter.
Simvastatin, lovastatin
Brilinta will result in higher serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg. See Pharmacology.
Digoxin
Digoxin: Because of inhibition of the P-glycoprotein transporter, monitor digoxin levels with initiation of or any change in ticagrelor therapy. See Pharmacology
Other Concomitant Therapy
BRILINTA can be administered with unfractionated or low-molecular-weight heparin, GPIIb/IIIa inhibitors, proton pump inhibitors, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): 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).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ticagrelor in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Ticagrelor during labor and delivery.
Nursing Mothers
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.
Pediatric Use
The safety and effectiveness of BRILINTA in pediatric patients have not been established.
Geriatic Use
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.
Gender
There is no FDA guidance on the use of Ticagrelor with respect to specific gender populations.
Race
There is no FDA guidance on the use of Ticagrelor with respect to specific racial populations.
Renal Impairment
No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied [see Clinical Pharmacology (12.3)].
Hepatic Impairment
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 (4), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ticagrelor in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Ticagrelor in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Ticagrelor Administration in the drug label.
Monitoring
There is limited information regarding Ticagrelor Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Ticagrelor and IV administrations.
Overdosage
There is limited information regarding Ticagrelor overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Ticagrelor Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Ticagrelor Mechanism of Action in the drug label.
Structure
There is limited information regarding Ticagrelor Structure in the drug label.
Pharmacodynamics
There is limited information regarding Ticagrelor Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Ticagrelor Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Ticagrelor Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Ticagrelor Clinical Studies in the drug label.
How Supplied
There is limited information regarding Ticagrelor How Supplied in the drug label.
Storage
There is limited information regarding Ticagrelor Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Ticagrelor Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Ticagrelor interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Ticagrelor Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Ticagrelor Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.