Products1
Detailed information about drug products covered under this FDA approval, including NDC codes, dosage forms, ingredients, and administration routes.
BRILINTA
Product Details
Drug Labeling Information
Complete FDA-approved labeling information including indications, dosage, warnings, contraindications, and other essential prescribing details.
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
Package/Label Display Panel
Brilinta®
Ticagrelor Tablets
90 mg
Contains Approximately 1440 Tablets
RECENT MAJOR CHANGES SECTION
RECENT MAJOR CHANGES
Warnings and Precautions (5.7) 08/2021
DESCRIPTION SECTION
11 DESCRIPTION
BRILINTA contains ticagrelor, a cyclopentyltriazolopyrimidine, inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP-receptor. Chemically it is (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. The empirical formula of ticagrelor is C23H28F2N6O4S and its molecular weight is 522.57. The chemical structure of ticagrelor is:
Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 μg/mL at room temperature.
BRILINTA 90 mg tablets for oral administration contain 90 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellow.
BRILINTA 60 mg tablets for oral administration contain 60 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol 400, ferric oxide black, and ferric oxide red.
CLINICAL PHARMACOLOGY SECTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.
12.2 Pharmacodynamics
The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6-week study examining both acute and chronic platelet inhibition effects in response to 20 μM ADP as the platelet aggregation agonist.
The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. As shown in Figure 5, IPA was higher in the ticagrelor group at all time points. The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least 8 hours.
The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP.
As shown in Figure 6, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 6 shows that after 24 hours, IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%), indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk or thrombotic risk track with IPA, for either ticagrelor or clopidogrel.
Figure 5 - Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel
Figure 6 - Mean inhibition of platelet aggregation (IPA) following 6 weeks on placebo, ticagrelor 90 mg twice daily, or clopidogrel 75 mg daily
Transitioning from clopidogrel to BRILINTA resulted in an absolute IPA increase of 26.4% and from BRILINTA to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to BRILINTA without interruption of antiplatelet effect [see Dosage and Administration (2)].
12.3 Pharmacokinetics
Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers.
Absorption
BRILINTA can be taken with or without food. Absorption of ticagrelor occurs with a median tmax of 1.5 h (range 1.0–4.0). The formation of the major circulating metabolite AR-C124910XX (active) from ticagrelor occurs with a median tmax of 2.5 h (range 1.5-5.0).
The mean absolute bioavailability of ticagrelor is about 36% (range 30%-42%). Ingestion of a high-fat meal had no effect on ticagrelor Cmax, but resulted in a 21% increase in AUC. The Cmax of its major metabolite was decreased by 22% with no change in AUC.
BRILINTA as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and Cmax within 80-125% for ticagrelor and AR-C124910XX) with a median tmax of 1.0 hour (range 1.0 – 4.0) for ticagrelor and 2.0 hours (range 1.0 –8.0) for AR-C124910XX.
Distribution
The steady state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%).
Metabolism
CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-40% of the exposure of ticagrelor.
Excretion
The primary route of ticagrelor elimination is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion. The mean t1/2 is approximately 7 hours for ticagrelor and 9 hours for the active metabolite.
Specific Populations
The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented in Figure 7. Effects are modest and do not require dose adjustment.
Patients with End-Stage Renal Disease on Hemodialysis
In patients with end stage renal disease on hemodialysis AUC and Cmax of BRILINTA 90 mg administered on a day without dialysis were 38% and 51% higher respectively, compared to subjects with normal renal function. A similar increase in exposure was observed when BRILINTA was administered immediately prior to dialysis showing that BRILINTA is not dialyzable. Exposure of the active metabolite increased to a lesser extent. The IPA effect of BRILINTA was independent of dialysis in patients with end stage renal disease and similar to healthy adults with normal renal function.
Figure 7 - Impact of intrinsic factors on the pharmacokinetics of ticagrelor
Effects of Other Drugs on BRILINTA
CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. The effects of other drugs on the pharmacokinetics of ticagrelor are presented in Figure 8 as change relative to ticagrelor given alone (test/reference). Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) substantially increase ticagrelor exposure. Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem). CYP3A inducers (e.g., rifampin) substantially reduce ticagrelor blood levels. P-gp inhibitors (e.g., cyclosporine) increase ticagrelor exposure.
Co-administration of 5 mg intravenous morphine with 180 mg loading dose of ticagrelor decreased observed mean ticagrelor exposure by up to 25% in healthy adults and up to 36% in ACS patients undergoing PCI. Tmax was delayed by 1-2 hours. Exposure of the active metabolite decreased to a similar extent. Morphine co-administration did not delay or decrease platelet inhibition in healthy adults. Mean platelet aggregation was higher up to 3 hours post loading dose in ACS patients co-administered with morphine.
Co-administration of intravenous fentanyl with 180 mg loading dose of ticagrelor in ACS patients undergoing PCI resulted in similar effects on ticagrelor exposure and platelet inhibition.
Figure 8 - Effect of co-administered drugs on the pharmacokinetics of ticagrelor
*See Dosage and Administration (2)
Effects of BRILINTA on Other Drugs
In vitro metabolism studies demonstrate that ticagrelor and its major active metabolite are weak inhibitors of CYP3A4, potential activators of CYP3A5 and inhibitors of the P-gp transporter. Ticagrelor and AR-C124910XX were shown to have no inhibitory effect on human CYP1A2, CYP2C19, and CYP2E1 activity. For specific in vivo effects on the pharmacokinetics of simvastatin, atorvastatin, ethinyl estradiol, levonorgesterol, tolbutamide, digoxin and cyclosporine, see Figure 9.
Figure 9 - Impact of BRILINTA on the pharmacokinetics of co-administered drugs
12.5 Pharmacogenetics
In a genetic substudy cohort of PLATO, the rate of thrombotic CV events in the BRILINTA arm did not depend on CYP2C19 loss of function status.
DOSAGE FORMS & STRENGTHS SECTION
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60 mg and 90 mg tablets (3)
3 DOSAGE FORMS AND STRENGTHS
BRILINTA (ticagrelor) 90 mg is supplied as a round, biconvex, yellow, film- coated tablet marked with a “90” above “T” on one side.
BRILINTA (ticagrelor) 60 mg is supplied as a round, biconvex, pink, film- coated tablet marked with “60” above “T” on one side.
CONTRAINDICATIONS SECTION
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History of intracranial hemorrhage. (4.1)
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Active pathological bleeding. (4.2)
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Hypersensitivity to ticagrelor or any component of the product. (4.3)
4 CONTRAINDICATIONS
4.1 History of 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 [see Clinical Studies (14.1), (14.2)].
4.2 Active Bleeding
BRILINTA is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
4.3 Hypersensitivity
BRILINTA is contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product.
Boxed Warning section
WARNING: (A) BLEEDING RISK, and (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESS
IN PATIENTS WITH ACS
See full prescribing information for complete boxed warning.
BLEEDING RISK
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**BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding.****(5.1****,****6.1)**
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**Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage.****(4.1****,****4.2)**
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**Do not start BRILINTA in patients undergoing urgent coronary artery bypass graft surgery (CABG).****(5.1****,****6.1)**
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**If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events.****(5.4)**
ASPIRIN DOSE AND BRILINTA EFFECTIVENESS IN PATIENTS WITH ACS
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**Maintenance doses of aspirin above 100 mg daily reduce the effectiveness of BRILINTA and should be avoided.****(2****,****5.2****,****14.1)**
USE IN SPECIFIC POPULATIONS SECTION
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Lactation: Breastfeeding not recommended. (8.2)
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Available data from case reports with BRILINTA use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Ticagrelor given to pregnant rats and pregnant rabbits during organogenesis caused structural abnormalities in the offspring at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. When ticagrelor was given to rats during late gestation and lactation, pup death and effects on pup growth were seen at approximately 10 times the MRHD (see DATA).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. 20 mg/kg/day is 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. At the mid-dose of 100 mg/kg/day (5.5 times the MRHD on a mg/m2 basis), delayed development of liver and skeleton was seen. 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).
8.2 Lactation
Risk Summary
There are no data on the presence of ticagrelor or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Ticagrelor and its metabolites were present in rat milk at higher concentrations than in maternal plasma. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Breastfeeding is not recommended during treatment with BRILINTA.
8.4 Pediatric Use
The safety and effectiveness of BRILINTA have not been established in pediatric patients. Effectiveness was not demonstrated in an adequate and well-controlled study conducted in 101 BRILINTA-treated pediatric patients, aged 2 to <18 for reducing the rate of vaso-occlusive crises in sickle cell disease.
8.5 Geriatric Use
About half of the patients in PLATO, PEGASUS, THEMIS, and THALES were ≥65 years of age and at least 15% were ≥75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients.
8.6 Hepatic Impairment
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. No dosage adjustment is needed in patients with mild hepatic impairment [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].
8.7 Renal Impairment
No dosage adjustment is needed in patients with renal impairment [see Clinical Pharmacology (12.3)].
Patients with End-Stage Renal Disease on dialysis
Clinical efficacy and safety studies with BRILINTA did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, no clinically significant difference in concentrations of ticagrelor and its metabolite and platelet inhibition are expected compared to those observed in patients with normal renal function [see Clinical Pharmacology (12.3)]. It is not known whether these concentrations will lead to similar efficacy and safety in patients with ESRD on dialysis as were seen in PLATO, PEGASUS, THEMIS and THALES.
OVERDOSAGE SECTION
10 OVERDOSAGE
There is currently no known treatment to reverse the effects of BRILINTA, and ticagrelor is not dialyzable. Treatment of overdose should follow local standard medical practice. Bleeding is the expected pharmacologic effect of overdosing. If bleeding occurs, appropriate supportive measures should be taken.
Platelet transfusion did not reverse the antiplatelet effect of BRILINTA in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding.
Other effects of overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG.
INFORMATION FOR PATIENTS SECTION
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Advise patients daily doses of aspirin should not exceed 100 mg and to avoid taking any other medications that contain aspirin.
Advise patients that they:
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Will bleed and bruise more easily
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Will take longer than usual to stop bleeding
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Should report any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine.
Advise patients to contact their doctor if they experience unexpected shortness of breath, especially if severe.
Advise patients to inform physicians and dentists that they are taking BRILINTA before any surgery or dental procedure.
Advise women that breastfeeding is not recommended during treatment with BRILINTA [see Use in Specific Populations (8.2)].
BRILINTA® is a trademark of the AstraZeneca group of companies.
Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850
Distributed By:
Cardinal Health
Dublin, OH 43017
L50533760124
L7198 Rev. A
© AstraZeneca 2022
SPL MEDGUIDE SECTION
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MEDICATION GUIDE BRILINTA® (brih-LIN-tah) (ticagrelor) Tablets |
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What is the most important information I should know about BRILINTA? BRILINTA is used to lower your chance of having, or dying from, a heart attack or stroke.BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death. In cases of serious bleeding, such as internal bleeding, the bleeding may result in the need for blood transfusions or surgery. While you take BRILINTA: • • • Call your doctor right away, if you have any of these signs or symptoms of bleeding while taking BRILINTA: • • • • • Do not stop taking BRILINTA without talking to the doctor who prescribes it for you. People who are treated with a stent, and stop taking BRILINTA too soon, have a higher risk of getting a blood clot in the stent, having a heart attack, or dying. If you stop BRILINTA because of bleeding, or for other reasons, your risk of a heart attack or stroke may increase. Your doctor may instruct you to stop taking BRILINTA 5 days before surgery. This will help to decrease your risk of bleeding with your surgery or procedure. Your doctor should tell you when to start taking BRILINTA again, as soon as possible after surgery. Taking BRILINTA with aspirin BRILINTA is taken with aspirin. Talk to your doctor about the dose of aspirin that you should take with BRILINTA. In most cases, you should not take a dose of aspirin higher than 100 mg daily because it can affect how well BRILINTA works. Do not take doses of aspirin higher than what your doctor tells you to take. Tell your doctor if you take other medicines that contain aspirin, and do not take new over-the-counter medicines with aspirin in them. |
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What is BRILINTA? BRILINTA is a prescription medicine used to: • • • It is not known if BRILINTA is safe and effective in children. |
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Do not take BRILINTA if you: • • • |
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Before taking BRILINTA, tell your doctor about all of your medical conditions, if you: • • • • • • • • • Tell all of your doctors and dentists that you are taking BRILINTA. They should talk to the doctor who prescribed BRILINTA for you before you have any surgery or invasive procedure. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.BRILINTA may affect the way other medicines work, and other medicines may affect how BRILINTA works. Especially tell your doctor if you take: • • • • • • • • • Ask your doctor or pharmacist if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. |
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How should I take BRILINTA? • • • • • • • • |
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What are the possible side effects of BRILINTA? BRILINTA can cause serious side effects, including: • • • These are not all of the possible side effects of BRILINTA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
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How should I store BRILINTA? • Keep BRILINTA and all medicines out of the reach of children. |
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General information about the safe and effective use of BRILINTA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BRILINTA for a condition for which it was not prescribed. Do not give BRILINTA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about BRILINTA that is written for health professionals. |
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What are the ingredients in BRILINTA? Active ingredient: ticagrelor. 90 mg tablets: 60 mg tablets: Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 Distributed By: Cardinal Health Dublin, OH 43017 L50533760124 L7198 Rev. A For more information call 1-800-236-9933 or go to www.Brilinta.com. |
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 08/2021