Can You Take Brillinta With Coated Baby Aspirin

What is Brilinta and how is it used?

Brilinta is a prescription medicine used to:

• decrease your chance of death, eye attack, and stroke in people with a blockage of blood flow to the heart (acute coronary syndrome or ACS) or a history of a heart assault. Brilinta can also decrease your risk of blood clots in your stent in people who have received stents for the handling of ACS.
• decrease your risk of a first center attack or stroke in people who have a status where the claret menstruation to the eye is decreased (coronary artery disease or CAD) who are at high take a chance for having a middle assail or stroke.

It is not known if Brilinta is safe and constructive in children.

What are the possible side furnishings of Brilinta?

Brilinta tin can crusade serious side effects, including:

• See "What is the almost important information I should know about Brilinta?"
• Shortness of breath. Call your doctor if you take new or unexpected shortness of jiff when you are at rest, at night, or when you lot are doing any activity. Your md can determine what handling is needed.

These are non all of the possible side effects of Brilinta.

Phone call your doctor for medical advice about side effects. You may report side furnishings to FDA at 1-800-FDA-1088.

WARNING

(A) BLEEDING RISK, (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

1. Bleeding Risk
   • BRILINTA, similar other antiplatelet agents, tin can cause significant, sometimes fatal bleeding.
   • Do not use BRILINTA in patients with agile pathological bleeding or a history of intracranial hemorrhage.
   • Practice not start BRILINTA in patients undergoing urgent coronary artery featherbed graft surgery (CABG).
   • If possible, manage haemorrhage without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events.
2. Aspirin Dose And Brilinta Effectiveness
   • Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided.

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-(three,iv-difluorophenyl)cyclopropyl]amino}-5(propylthio)-3H-[ane,2,iii]-triazolo[4,five-d]pyrimidin-3-yl]-5-(ii-hydroxyethoxy)cyclopentane-i,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 comprise xc 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 comprise 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 blackness, and ferric oxide red.

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INDICATIONS

Astute Coronary Syndrome Or A History Of Myocardial Infarction

BRILINTA is indicated to reduce the risk of cardiovascular (CV) death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. For at to the lowest degree the first 12 months post-obit ACS, it is superior to clopidogrel.

BRILINTA also reduces the adventure of stent thrombosis in patients who take been stented for treatment of ACS [meet Clinical Studies].

Coronary Avenue Disease Simply No Prior Stroke Or Myocardial Infarction

BRILINTA is indicated to reduce the risk of a first MI or stroke in patients with coronary artery disease (CAD) at high risk for such events [see Clinical Studies]. While utilize is not limited to this setting, the efficacy of BRILINTA was established in a population with type 2 diabetes mellitus (T2DM).

Acute Ischemic Stroke Or Transient Ischemic Set on (TIA)

BRILINTA is indicated to reduce the risk of stroke in patients with astute ischemic stroke (NIH Stroke Scale score ≤5) or high-risk transient ischemic assail (TIA) [see Clinical Studies].

QUESTION

In the U.S., 1 in every 4 deaths is caused by heart affliction. Run across Answer

DOSAGE AND Assistants

Astute Coronary Syndrome Or A History Of Myocardial Infarction

Initiate treatment with a 180 mg loading dose of BRILINTA. Administer xc mg of BRILINTA twice daily during the showtime twelvemonth after an ACS event. After one yr, administrate 60 mg of BRILINTA twice daily.

Apply BRILINTA with a daily maintenance dose of aspirin of 75 to 100 mg [encounter WARNINGS AND PRECAUTIONS and Clinical Studies].

Coronary Avenue Affliction Just No Prior Stroke Or Myocardial Infarction

Administer sixty mg of BRILINTA twice daily. For all patients with ACS meet Astute Coronary Syndrome Or A History Of Myocardial Infarction.

Utilise BRILINTA with a daily maintenance dose of aspirin of 75 to 100 mg [run into WARNINGS AND PRECAUTIONS and Clinical Studies].

Acute Ischemic Stroke Or Transient Ischemic Attack (TIA)

Initiate treatment with a 180 mg loading dose of BRILINTA and then go along with 90 mg twice daily for up to 30 days.

The handling upshot accrued early in the course of therapy [see Clinical Studies].

Use BRILINTA with a loading dose of aspirin (300 to 325 mg) and a daily maintenance dose of aspirin of 75 to 100 mg [see WARNINGS AND PRECAUTIONS and Clinical Studies].

Administration

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

For patients who are unable to eat tablets whole, BRILINTA tablets can be crushed, mixed with water and boozer.

The mixture tin can too be administered via a nasogastric tube (CH8 or greater) [see CLINICAL PHARMACOLOGY].

Do non administer BRILINTA with another oral P2Y₁₂ platelet inhibitor.

HOW SUPPLIED

Dosage Forms And Strengths

BRILINTA (ticagrelor) 90 mg is supplied as a round, biconvex, yellow, film-coated tablet marked with a "ninety" in a higher place "T" on one side.

BRILINTA (ticagrelor) 60 mg is supplied as a circular, biconvex, pink, flick-coated tablet marked with "sixty" above "T" on one side.

BRILINTA (ticagrelor) xc mg is supplied as a round, biconvex, yellow, moving picture-coated tablet with a "ninety" to a higher place "T" on one side:

Bottles of threescore – NDC 0186-0777-threescore
100 count Infirmary Unit Dose – NDC 0186-0777-39

BRILINTA (ticagrelor) 60 mg is supplied as a round, arched, pink, motion-picture show-coated tablet with a "sixty" above "T" on one side:

Bottles of 60 – NDC 0186-0776-threescore

Storage And Handling

Shop at 25°C (77°F); excursions permitted to fifteen° to 30°C (59° to 86°F) [meet USP controlled room temperature].

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. Revised: February 2021

SIDE Furnishings

The following adverse reactions are also discussed elsewhere in the labeling:

• Bleeding [come across WARNINGS AND PRECAUTIONS]
• Dyspnea [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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 reverberate the rates observed in practice.

BRILINTA has been evaluated for safety in more than 58,000 patients.

Bleeding In PLATO (Reduction In Hazard Of Thrombotic Events In ACS)

Effigy 1 is a plot of time to the first non-CABG major haemorrhage result.

Effigy i - Kaplan-Meier estimate of time to first non-CABG PLATO-divers major haemorrhage issue (PLATO)

Frequency of haemorrhage in PLATO is summarized in Tables 1 and two. About half of the non-CABG major bleeding events were in the first xxx days.

Table 1 – Non-CABG related bleeds (PLATO)

	BRILINTA* N=9235	Clopidogrel N=9186
	n (%) patients with event	n (%) patients with result
PLATO Major + Modest	713 (7.vii)	567 (6.2)
Major	362 (three.ix)	306 (3.three)
Fatal/Life-threatening	171 (1.9)	151 (one.6)
Fatal	15 (0.two)	16 (0.2)
Intracranial hemorrhage (Fatal/Life-threatening)	26 (0.three)	15 (0.2)
PLATO Minor drain: requires medical intervention to stop or care for bleeding. PLATO Major drain: any i of the following: fatal; intracranial; intrapericardial with cardiac tamponade; hypovolemic shock or severe hypotension requiring intervention; significantly disabling (e.thousand., intraocular with permanent vision loss); associated with a decrease in Hb of at to the lowest degree three thousand/dL (or a autumn in hematocrit (Hct) of at least 9%); transfusion of 2 or more units. PLATO Major drain, fatal/life-threatening: any major bleed equally described above and associated with a decrease in Hb of more than 5 g/dL (or a fall in hematocrit (Hct) of at to the lowest degree 15%); transfusion of 4 or more than units. Fatal: A bleeding event that directly led to decease within 7 days.
* xc mg BID

No baseline demographic cistron altered the relative risk of haemorrhage with BRILINTA compared to clopidogrel.

In PLATO, 1584 patients underwent CABG surgery. The percentages of those patients who bled are shown in Figure 2 and Table two.

Figure 2 – 'Major fatal/life-threatening' CABG-related haemorrhage by days from last dose of study drug to CABG process (PLATO)

X-centrality is days from last dose of report drug prior to CABG. The PLATO protocol recommended a procedure for withholding report drug prior to CABG or other major surgery without unblinding. If surgery was elective or non-urgent, study drug was interrupted temporarily, as follows: If local practice was to allow antiplatelet effects to misemploy before surgery, capsules (blinded clopidogrel) were withheld five days before surgery and tablets (blinded ticagrelor) were withheld for a minimum of 24 hours and a maximum of 72 hours before surgery. If local practice was to perform surgery without waiting for dissipation of antiplatelet furnishings capsules and tablets were withheld 24 hours prior to surgery and use of aprotinin or other haemostatic agents was allowed. If local practise was to use IPA monitoring to decide when surgery could be performed both the capsules and tablets were withheld at the same time and the usual monitoring procedures followed. T Ticagrelor; C Clopidogrel.

Table 2 – CABG-related haemorrhage (PLATO)

	BRILINTA* N=770	Clopidogrel N=814
	n (%) patients with event	due north (%) patients with event
PLATO Total Major	626 (81.3)	666 (81.eight)
Fatal/Life-threatening	337 (43.viii)	350 (43.0)
Fatal	vi (0.8)	vii (0.9)
PLATO Major bleed: any 1 of the following: fatal; intracranial; intrapericardial with cardiac tamponade; hypovolemic stupor or severe hypotension requiring intervention; significantly disabling (east.1000., intraocular with permanent vision loss); associated with a subtract in Hb of at to the lowest degree 3 m/dL (or a fall in hematocrit (Hct) of at least 9%); transfusion of two or more units. PLATO Major bleed, fatal/life-threatening: whatsoever major drain as described above and associated with a decrease in Hb of more than than 5 g/dL (or a fall in hematocrit (Hct) of at least 15%); transfusion of iv or more units.
* xc mg BID

When antiplatelet therapy was stopped v days before CABG, major bleeding occurred in 75% of BRILINTA treated patients and 79% on clopidogrel.

Other Adverse Reactions In PLATO

Adverse reactions that occurred at a charge per unit of iv% or more in PLATO are shown in Table 3.

Tabular array iii – Per centum of patients reporting not-hemorrhagic adverse reactions at to the lowest degree 4% or more in either group and more frequently on BRILINTA (PLATO)

	BRILINTA* N=9235	Clopidogrel N=9186
Dyspnea	13.8	7.8
Dizziness	4.5	3.9
Nausea	4.3	iii.8
* xc mg BID

Bleeding In PEGASUS (Secondary Prevention In Patients With A History Of Myocardial Infarction)

Overall outcome of haemorrhage events in the PEGASUS study are shown in Table iv.

Table iv – Haemorrhage events (PEGASUS)

	BRILINTA* N=6958	Placebo N=6996
	Events / 1000 patient years	Events / 1000 patient years
TIMI Major	8	three
Fatal	1	ane
Intracranial hemorrhage	2	1
TIMI Major or Minor	11	5
TIMI Major: Fatal bleeding, OR whatever intracranial bleeding, OR clinically overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥5 g/dL, or a fall in hematocrit (Hct) of ≥15%. Fatal: A bleeding event that directly led to decease within seven days. TIMI Modest: Clinically apparent with iii-5 g/dL decrease in hemoglobin. * lx mg BID

The bleeding profile of BRILINTA 60 mg compared to aspirin alone was consistent across multiple pre-defined subgroups (e.grand., past age, gender, weight, race, geographic region, concurrent conditions, concomitant therapy, stent, and medical history) for TIMI Major and TIMI Major or Small-scale bleeding events.

Other Agin Reactions In PEGASUS

Agin reactions that occurred in PEGASUS at rates of 3% or more are shown in Table 5.

Tabular array 5 – Non-hemorrhagic agin reactions reported in >3.0% of patients in the ticagrelor 60 mg treatment group (PEGASUS)

	BRILINTA* Due north=6958	Placebo Northward=6996
Dyspnea	fourteen.2%	5.5%
Dizziness	4.five%	4.1%
Diarrhea	three.3%	ii.5%
*lx mg BID

Bleeding In THEMIS (Prevention Of Major CV Events In Patients With CAD And Type 2 Diabetes Mellitus)

The Kaplan-Meier bend of time to offset TIMI Major haemorrhage event is presented in Figure 3.

Figure three - Time to kickoff TIMI Major bleeding event (THEMIS)

T = Ticagrelor; P = Placebo; N = Number of patients

The bleeding events in THEMIS are shown below in Table 6.

Table 6 – Bleeding events (THEMIS)

	BRILINTA N=9562	Placebo Due north=9531
	Events / one thousand patient years	Events / 1000 patient years
TIMI Major	ix	4
TIMI Major or Minor	12	v
TIMI Major or Small or Requiring medical attending	46	18
Fatal bleeding	i	0
Intracranial hemorrhage	3	2

Bleeding In THALES (Reduction In Risk Of Stroke In Patients With Acute Ischemic Stroke Or TIA)

The Kaplan-Meier curve of fourth dimension course of GUSTO severe bleeding events is presented in Figure 4.

Figure 4 - Time course of GUSTO astringent bleeding events

KM%: Kaplan-Meier pct evaluated at Day xxx; T = Ticagrelor; P = placebo; N = Number of patients GUSTO Severe: Any one of the following: fatal bleeding, intracranial haemorrhage (excluding asymptomatic hemorrhagic transformations of ischemic brain infarctions and excluding microhemorrhages < 10 mm evident only on gradient-echo magnetic resonance imaging), bleeding that caused hemodynamic compromise requiring intervention (eg, systolic blood pressure <90 mmg Hg that required blood or fluid replacement, or vasopressor/inotropic support, or surgical intervention).

Intracranial Haemorrhage and Fatal Haemorrhage in THALES

In total, there were 21 intracranial hemorrhages (ICHs) for BRILINTA and half-dozen ICHs for placebo. Fatal bleedings, nearly all ICH, occurred in 11 for BRILINTA and in ii for placebo.

Bradycardia

In a Holter substudy of nearly 3000 patients in PLATO, more patients had ventricular pauses with BRILINTA (6.0%) than with clopidogrel (iii.v%) in the acute stage; rates were ii.2% and ane.6%, respectively, after 1 calendar month. PLATO, PEGASUS, THEMIS and THALES excluded patients at increased risk of bradycardic events (e.thousand., patients who accept sick sinus syndrome, two^nd or iii^rd degree AV block, or bradycardic-related syncope and non protected with a pacemaker).

Lab Abnormalities

Serum Uric Acrid

In PLATO, serum uric acrid levels increased approximately 0.6 mg/dL from baseline on BRILINTA xc mg and approximately 0.ii mg/dL on clopidogrel. The divergence disappeared within 30 days of discontinuing treatment. Reports of gout did non differ between treatment groups in PLATO (0.6% in each group).

In PEGASUS, serum uric acrid levels increased approximately 0.2 mg/dL from baseline on BRILINTA 60 mg and no height was observed on aspirin alone. Gout occurred more commonly in patients on BRILINTA than in patients on aspirin alone (ane.5%, ane.1%). Hateful serum uric acid concentrations decreased afterward treatment was stopped.

Serum Creatinine

In PLATO, a >fifty% increase in serum creatinine levels was observed in 7.4% of patients receiving BRILINTA ninety mg compared to 5.9% of patients receiving clopidogrel. The increases typically did non progress with ongoing treatment and frequently decreased with connected therapy. Evidence of reversibility upon discontinuation was observed fifty-fifty in those with the greatest on handling increases. Treatment groups in PLATO did not differ for renal-related serious agin events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria.

In PEGASUS, serum creatinine concentration increased by >50% in approximately 4% of patients receiving BRILINTA 60 mg, similar to aspirin alone. The frequency of renal related adverse events was like for ticagrelor and aspirin alone regardless of age and baseline renal function.

Postmarketing Feel

The following adverse reactions have been identified during mail service-approval utilise 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 human relationship to drug exposure.

Blood and lymphatic system disorders: Thrombotic Thrombocytopenic Purpura (TTP) has been rarely reported with the use of BRILINTA. TTP is a serious status which tin can occur after a brief exposure (<2 weeks) and requires prompt handling.

Immune system disorders: Hypersensitivity reactions including angioedema [encounter CONTRAINDICATIONS].

Respiratory Disorders: Key slumber apnea, Cheyne-Stokes respiration

Skin and subcutaneous tissue disorders: Rash

IMAGES

See Images

DRUG INTERACTIONS

Stiff CYP3A Inhibitors

Strong CYP3A inhibitors essentially increase ticagrelor exposure and then increment the risk of dyspnea, bleeding, and other adverse events. Avoid use of potent inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin) [encounter CLINICAL PHARMACOLOGY].

Potent CYP3A Inducers

Stiff CYP3A inducers substantially reduce ticagrelor exposure and and so decrease the efficacy of ticagrelor. Avert use with stiff inducers of CYP3A (e.thou., rifampin, phenytoin, carbamazepine and phenobarbital) [see CLINICAL PHARMACOLOGY].

Aspirin

Use of BRILINTA with aspirin maintenance doses in a higher place 100 mg reduced the effectiveness of BRILINTA [see WARNINGS AND PRECAUTIONS and Clinical Studies].

Opioids

As with other oral P2Y₁₂ inhibitors, co-assistants of opioid agonists filibuster and reduce the assimilation of ticagrelor and its agile metabolite presumably considering of slowed gastric emptying [encounter CLINICAL PHARMACOLOGY]. Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

Simvastatin, Lovastatin

BRILINTA increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than twoscore mg [see CLINICAL PHARMACOLOGY].

Digoxin

BRILINTA inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in BRILINTA therapy [see CLINICAL PHARMACOLOGY].

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Risk Of Bleeding

Drugs that inhibit platelet function including BRILINTA increase the take chances of bleeding [come across ADVERSE REACTIONS and Discontinuation Of BRILINTA In Patients Treated For Coronary Avenue Disease].

Patients Treated For Astute Ischemic Stroke Or TIA

Patients at NIHSS >5 and patients receiving thrombolysis were excluded from THALES and use of BRILINTA in such patients is not recommended.

Concomitant Aspirin Maintenance Dose For Patients Beingness Treated For ACS

In the management of patients with ACS, the use of BRILINTA with maintenance doses of aspirin in a higher place 100 mg decreased the effectiveness of BRILINTA. In such patients, utilise a maintenance dose of aspirin of 75-100 mg [see DOSAGE AND Assistants and Clinical Studies].

Dyspnea

In clinical trials, about 14% (PLATO and PEGASUS) to 21% (THEMIS) of patients treated with BRILINTA developed dyspnea. Dyspnea was normally mild to moderate in intensity and often resolved during continued treatment but led to study drug discontinuation in 0.ix% (PLATO), 1.0% (THALES), 4.3% (PEGASUS), and half-dozen.nine% (THEMIS) of patients.

In a substudy of PLATO, 199 subjects underwent pulmonary part testing irrespective of whether they reported dyspnea. There was no indication of an adverse effect on pulmonary function assessed after one month or later at least six months of chronic treatment.

If a patient develops new, prolonged, or worsened dyspnea that is determined to exist related to BRILINTA, no specific treatment is required; continue BRILINTA without pause if possible. In the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing some other antiplatelet agent.

Discontinuation Of BRILINTA In Patients Treated For Coronary Artery Disease

Discontinuation of BRILINTA volition increase the risk of myocardial infarction, stroke, and death in patients beingness treated for coronary avenue disease. If BRILINTA must be temporarily discontinued (due east.g., to care for bleeding or for significant surgery), restart it equally soon as possible. When possible, interrupt therapy with BRILINTA for five days prior to surgery that has a major risk of bleeding. Resume BRILINTA as before long as hemostasis is achieved.

Bradyarrhythmias

BRILINTA can cause ventricular pauses [see Agin REACTIONS]. Bradyarrhythmias including AV cake have been reported in the postmarketing setting. Patients with a history of sick sinus syndrome, 2^nd or three^rd caste AV cake or bradycardia-related syncope not protected by a pacemaker were excluded from clinical studies and may exist at increased risk of developing bradyarrhythmias with ticagrelor.

Astringent Hepatic Impairment

Avoid utilize of BRILINTA in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor. There are no studies of BRILINTA patients with severe hepatic impairment [see CLINICAL PHARMACOLOGY].

Laboratory Test Interferences

False Negative Functional Tests For Heparin Induced Thrombocytopenia (Hitting)

BRILINTA has been reported to cause false negative results in platelet functional tests (to include, but may non be limited to, the heparin-induced platelet aggregation (HIPA) assay) for patients with Heparin Induced Thrombocytopenia (HIT). This is related to inhibition of the P2Y₁₂-receptor on the salubrious donor platelets in the examination by ticagrelor in the affected patient'due south serum/plasma. Information on concomitant treatment with BRILINTA is required for interpretation of Hit functional tests. Based on the mechanism of BRILINTA interference, BRILINTA is non expected to impact PF4 antibiotic testing for HIT.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Advise patients daily doses of aspirin should non exceed 100 mg and to avoid taking whatsoever other medications that comprise aspirin.

Advise patients that they:

• Will bleed and bruise more hands
• Will take longer than usual to end bleeding
• Should report any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine.

Propose patients to contact their doctor if they experience unexpected shortness of breath, especially if severe.

Propose patients to inform physicians and dentists that they are taking BRILINTA earlier whatsoever surgery or dental procedure.

Advise women that breastfeeding is not recommended during handling with BRILINTA [come across Utilize In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Ticagrelor was not carcinogenic in the mouse at doses up to 250 mg/kg/24-hour interval or in the male rat at doses upwardly to 120 mg/kg/day (19 and fifteen times the MRHD of 90 mg twice daily on the ground of AUC, respectively). Uterine carcinomas, uterine adenocarcinomas and hepatocellular adenomas were seen in female rats at doses of 180 mg/kg/twenty-four hours (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 person rats.

Mutagenesis

Ticagrelor did not demonstrate genotoxicity when tested in the Ames bacterial mutagenicity exam, mouse lymphoma assay and the rat micronucleus test. The active O-demethylated metabolite did non demonstrate genotoxicity in the Ames assay and mouse lymphoma analysis.

Damage Of Fertility

Ticagrelor had no issue on male fertility at doses upwardly to 180 mg/kg/24-hour interval or on female person fertility at doses upwards to 200 mg/kg/twenty-four hours (>15-fold the MRHD on the basis of AUC). Doses of ≥ten mg/kg/day given to female rats acquired an increased incidence of irregular duration oestrus cycles (1.v-fold the MRHD based on AUC).

Use In Specific Populations

Pregnancy

Take a chance Summary

Available data from case reports with BRILINTA use in significant women have not identified a drug-associated risk of major nascency defects, miscarriage, or adverse maternal or fetal outcomes. Ticagrelor given to pregnant rats and pregnant rabbits during organogenesis acquired structural abnormalities in the offspring at maternal doses most v 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 x times the MRHD (run into Information).

The estimated background gamble of major birth defects and miscarriage for the indicated population is unknown. All pregnancies take a background risk of birth defect, loss, or other agin outcomes. In the U.S. full general population, the estimated groundwork 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/mean solar day. 20 mg/kg/day is approximately the same as the MRHD of ninety mg twice daily for a 60 kg human on a mg/m² basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/twenty-four hours (xvi.v times the MRHD on a mg/m² basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced joint of pelvis, and misshapen/misaligned sternebrae. At the mid-dose of 100 mg/kg/day (five.5 times the MRHD on a mg/g² basis), delayed development of liver and skeleton was seen. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/twenty-four hours, fetuses exposed to the highest maternal dose of 63 mg/kg/mean solar 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 belatedly gestation and lactation. Pup death and furnishings on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m^two basis). Relatively minor effects such as delays in pinna unfolding and center opening occurred at doses of ten and 60 mg/kg (approximately ane-half and three.2 times the MRHD on a mg/k^two basis).

Lactation

Risk Summary

There are no data on the presence of ticagrelor or its metabolites in man 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 non recommended during treatment with BRILINTA.

Pediatric Apply

The safety and effectiveness of BRILINTA in pediatric patients have not been established.

Geriatric Use

Near half of the patients in PLATO, PEGASUS, THEMIS, and THALES were ≥65 years of age and at to the lowest degree fifteen% were ≥75 years of historic period. No overall differences in condom or effectiveness were observed between elderly and younger patients.

Hepatic Harm

Ticagrelor is metabolized past the liver and impaired hepatic function can increment risks for bleeding and other adverse events. Avert utilise of BRILINTA in patients with severe hepatic impairment. At that place is limited experience with BRILINTA in patients with moderate hepatic impairment; consider the risks and benefits of handling, noting the probable increase in exposure to ticagrelor. No dosage aligning is needed in patients with balmy hepatic impairment [come across WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Renal Impairment

No dosage adjustment is needed in patients with renal impairment [encounter CLINICAL PHARMACOLOGY].

Patients With End-Stage Renal Disease On Dialysis

Clinical efficacy and rubber studies with BRILINTA did not enroll patients with end-stage renal affliction (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 [run into CLINICAL PHARMACOLOGY]. It is not known whether these concentrations will pb to similar efficacy and safety in patients with ESRD on dialysis as were seen in PLATO, PEGASUS, THEMIS and THALES.

SLIDESHOW

Heart Disease: Symptoms, Signs, and Causes See Slideshow

Overdosage & Contraindications

OVERDOSE

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, advisable supportive measures should exist taken.

Platelet transfusion did non reverse the antiplatelet issue of BRILINTA in healthy volunteers and is unlikely to exist of clinical benefit in patients with bleeding.

Other effects of overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG.

CONTRAINDICATIONS

History Of Intracranial Hemorrhage

BRILINTA is contraindicated in patients with a history of intracranial hemorrhage (ICH) considering of a high take chances of recurrent ICH in this population [see Clinical Studies].

Agile Bleeding

BRILINTA is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Hypersensitivity

BRILINTA is contraindicated in patients with hypersensitivity (east.yard., angioedema) to ticagrelor or whatsoever component of the product.

CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

The inhibition of platelet aggregation (IPA) past ticagrelor and clopidogrel was compared in a 6-week study examining both astute and chronic platelet inhibition furnishings 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 Effigy 5, IPA was higher in the ticagrelor group at all fourth dimension points. The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least eight hours.

The showtime of IPA was examined after half-dozen weeks on ticagrelor ninety mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP.

As shown in Effigy 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 withal maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor grouping was like to IPA in the placebo group. It is not known how either bleeding adventure or thrombotic risk rails with IPA, for either ticagrelor or clopidogrel.

Figure 5 – Mean inhibition of platelet assemblage (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel

Effigy six – Mean inhibition of platelet aggregation (IPA) following 6 weeks on placebo, ticagrelor ninety 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 exist transitioned from clopidogrel to BRILINTA without pause of antiplatelet consequence [run across DOSAGE AND Assistants].

Pharmacokinetics

Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and salubrious volunteers.

Absorption

BRILINTA can be taken with or without nutrient. Assimilation 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 ii.5 h (range 1.5-5.0).

The hateful absolute bioavailability of ticagrelor is about 36% (range 30%-42%). Ingestion of a high-fat meal had no effect on ticagrelor Cmax, merely resulted in a 21% increment in AUC. The Cmax of its major metabolite was decreased by 22% with no change in AUC.

BRILINTA equally 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 fourscore-125% for ticagrelor and AR-C124910XX) with a median tmax of 1.0 hour (range ane.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 50. 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 agile metabolite. Ticagrelor and its major agile metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-xl% of the exposure of ticagrelor.

Excretion

The main 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 main road of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion. The hateful t1/2 is approximately seven hours for ticagrelor and nine hours for the active metabolite.

Specific Populations

The effects of age, gender, ethnicity, renal impairment and mild hepatic harm on the pharmacokinetics of ticagrelor are presented in Figure vii. Effects are pocket-sized and do non require dose aligning.

Patients With End-Phase Renal Disease On Hemodialysis

In patients with end stage renal affliction on hemodialysis AUC and Cmax of BRILINTA xc mg administered on a twenty-four hour period without dialysis were 38% and 51% college respectively, compared to subjects with normal renal role. A similar increment in exposure was observed when BRILINTA was administered immediately prior to dialysis showing that BRILINTA is non dialyzable. Exposure of the active metabolite increased to a lesser extent. The IPA consequence of BRILINTA was independent of dialysis in patients with end stage renal illness and like to healthy adults with normal renal part.

Figure seven – 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 furnishings of other drugs on the pharmacokinetics of ticagrelor are presented in Figure viii every bit change relative to ticagrelor given lone (test/reference). Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) essentially increase ticagrelor exposure. Moderate CYP3A inhibitors take lesser effects (e.g., diltiazem). CYP3A inducers (e.g., rifampin) substantially reduce ticagrelor blood levels. P-gp inhibitors (e.chiliad., cyclosporine) increase ticagrelor exposure.

Co-administration of 5 mg intravenous morphine with 180 mg loading dose of ticagrelor decreased observed mean ticagrelor exposure past upwardly to 25% in healthy adults and up to 36% in ACS patients undergoing PCI. Tmax was delayed by 1-ii hours. Exposure of the active metabolite decreased to a similar extent. Morphine co-administration did non 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-assistants 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

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 action. For specific in vivo furnishings on the pharmacokinetics of simvastatin, atorvastatin, ethinyl estradiol, levonorgesterol, tolbutamide, digoxin and cyclosporine, see Figure nine.

Figure 9 – Touch of BRILINTA on the pharmacokinetics of co-administered drugs

Pharmacogenetics

In a genetic substudy cohort of PLATO, the charge per unit of thrombotic CV events in the BRILINTA arm did not depend on CYP2C19 loss of function status.

Clinical Studies

Acute Coronary Syndromes And Secondary Prevention Afterward Myocardial Infarction

PLATO

PLATO (NCT00391872) was a randomized double-blind written report comparing BRILINTA (Northward=9333) to clopidogrel (N=9291), both given in combination with aspirin and other standard therapy, in patients with astute coronary syndromes (ACS), who presented within 24 hours of onset of the most recent episode of chest hurting or symptoms. The study's master endpoint was the composite of starting time occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke.

Patients who had already been treated with clopidogrel could be enrolled and randomized to either report handling. Patients with previous intracranial hemorrhage, gastrointestinal bleeding within the by six months, or with known haemorrhage diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. Patients could exist included whether there was intent to manage the ACS medically or invasively, just patient randomization was not stratified by this intent.

All patients randomized to BRILINTA received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. Patients in the clopidogrel arm were treated with an initial loading dose of clopidogrel 300 mg, if clopidogrel therapy had non already been given. Patients undergoing PCI could receive an boosted 300 mg of clopidogrel at investigator discretion. A daily maintenance dose of aspirin 75-100 mg was recommended, but higher maintenance doses of aspirin were immune according to local judgment. Patients were treated for at least 6 months and for upward to 12 months.

PLATO patients were predominantly male person (72%) and Caucasian (92%). Almost 43% of patients were >65 years and 15% were >75 years. Median exposure to written report drug was 276 days. About one-half of the patients received pre-report clopidogrel and nigh 99% of the patients received aspirin at some time during PLATO. Nigh 35% of patients were receiving a statin at baseline and 93% received a statin sometime during PLATO.

Tabular array 7 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. Separate secondary endpoint analyses are shown for the overall occurrence of CV death, MI, and stroke and overall bloodshed.

Tabular array seven – Patients with outcome events (PLATO)

	BRILINTA* N=9333	Clopidogrel Northward=9291	Hazard Ratio (95% CI)	p-value
	Events / 1000 patient years	Events / 1000 patient years
Composite of CV decease, MI, or stroke	111	131	0.84 (0.77, 0.92)	0.0003
CV decease	32	43	0.74
Non-fatal MI	64	76	0.84
Not-fatal stroke	15	12	1.24
Secondary endpoints†
CV expiry	45	57	0.79 (0.69, 0.91)	0.0013
MI‡	65	76	0.84 (0.75, 0.95)	0.0045
Stroke‡	sixteen	xiv	1.17 (0.91, 1.52)	0.22
All-cause mortality	51	65	0.78 (0.69, 0.89)	0.0003
*Dosed at xc mg bid. †Annotation: rates of first events for the components CV Decease, MI and Stroke are the bodily rates for offset events for each component and exercise non add up to the overall rate of events in the composite endpoint. ‡Including patients who could have had other non-fatal events or died.

The Kaplan-Meier curve (Figure 10) shows time to first occurrence of the primary composite endpoint of CV death, nonfatal MI or non-fatal stroke in the overall written report.

Figure x – Time to first occurrence of CV expiry, MI, or stroke (PLATO)

The curves split up by 30 days [relative risk reduction (RRR) 12%] and go on to diverge throughout the 12-month handling period (RRR 16%).

Amongst 11,289 patients with PCI receiving any stent during PLATO, at that place was a lower take chances of stent thrombosis (i.3% for adjudicated "definite") than with clopidogrel (1.9%) (Hour 0.67, 95% CI 0.50-0.91; p=0.009). The results were similar for drug-eluting and bare metal stents.

A wide range of demographic, concurrent baseline medications, and other handling differences were examined for their influence on upshot. Some of these are shown in Figure 11. Such analyses must be interpreted charily, as differences can reflect the play of run a risk amid a large number of analyses. Most of the analyses show effects consequent with the overall results, but there are ii exceptions: a finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin. These are considered further below.

Nigh of the characteristics shown are baseline characteristics, but some reverberate mail service-randomization determinations (eastward.thousand., aspirin maintenance dose, apply of PCI).

Figure 11 – Subgroup analyses of (PLATO)

Note: The figure above presents effects in diverse subgroups most of which are baseline characteristics and nearly of which were pre-specified. The 95% confidence limits that are shown do not accept into account how many comparisons were made, nor do they reflect the outcome of a detail cistron after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Regional Differences

Results in the rest of the world compared to effects in North America (US and Canada) bear witness a smaller consequence in Northward America, numerically inferior to the control and driven by the U.s.a. subset. The statistical test for the U.s.a./non-US comparison is statistically significant (p=0.009), and the same trend is present for both CV death and non-fatal MI. The individual results and nominal p-values, similar all subset analyses, need cautious estimation, and they could correspond gamble findings. The consistency of the differences in both the CV mortality and not-fatal MI components, nevertheless, supports the possibility that the finding is reliable.

A wide diverseness of baseline and procedural differences between the US and not-United states of america (including intended invasive vs. planned medical management, utilize of GPIIb/IIIa inhibitors, employ of drug eluting vs. blank-metallic stents) were examined to come across if they could business relationship for regional differences, but with one exception, aspirin maintenance dose, these differences did not appear to lead to differences in outcome.

Aspirin Dose

The PLATO protocol left the choice of aspirin maintenance dose up to the investigator and use patterns were different in US sites from sites outside of the Usa. About 8% of non-US investigators administered aspirin doses above 100 mg, and about 2% administered doses above 300 mg. In the The states, 57% of patients received doses above 100 mg and 54% received doses above 300 mg. Overall results favored BRILINTA when used with low maintenance doses (≤100 mg) of aspirin, and results analyzed past aspirin dose were similar in the Us and elsewhere. Figure 10 shows overall results past median aspirin dose. Figure 12 shows results past region and dose.

Figure 12 – CV expiry, MI, stroke by maintenance aspirin dose in the US and outside the Usa (PLATO)

Similar whatever unplanned subset analysis, especially one where the characteristic is not a truthful baseline characteristic (but may exist adamant by usual investigator practise), the above analyses must exist treated with caution. It is notable, yet, that aspirin dose predicts outcome in both regions with a like pattern, and that the pattern is similar for the two major components of the primary endpoint, CV death and non-fatal MI.

Despite the need to treat such results cautiously, in that location appears to be good reason to restrict aspirin maintenance dosage accompanying ticagrelor to 100 mg. College doses exercise non take an established benefit in the ACS setting, and there is a strong proffer that use of such doses reduces the effectiveness of BRILINTA.

PEGASUS

The PEGASUS TIMI-54 study (NCT01225562) was a 21,162-patient, randomized, double-blind, placebo-controlled, parallel-group study. Two doses of ticagrelor, either 90 mg twice daily or 60 mg twice daily, co-administered with 75- 150 mg of aspirin, were compared to aspirin therapy lonely in patients with history of MI. The primary endpoint was the composite of offset occurrence of CV death, non-fatal MI and non-fatal stroke. CV death and all-cause mortality were assessed as secondary endpoints.

Patients were eligible to participate if they were ≥50 years old, with a history of MI 1 to 3 years prior to randomization, and had at least one of the following risk factors for thrombotic cardiovascular events: age ≥65 years, diabetes mellitus requiring medication, at least one other prior MI, testify of multivessel coronary artery disease, or creatinine clearance <60 mL/min. Patients could be randomized regardless of their prior ADP receptor blocker therapy or a lapse in therapy. Patients requiring or who were expected to require renal dialysis during the study were excluded. Patients with whatever previous intracranial hemorrhage, gastrointestinal haemorrhage within the past six months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. A pocket-size number of patients with a history of stroke were included. Based on information external to PEGASUS, 102 patients with a history of stroke (90 of whom received written report drug) were terminated early and no further such patients were enrolled.

Patients were treated for at least 12 months and upwards to 48 months with a median follow up time of 33 months.

Patients were predominantly male person (76%) Caucasian (87%) with a mean age of 65 years, and 99.8% of patients received prior aspirin therapy.

The Kaplan-Meier curve (Effigy 13) shows time to start occurrence of the principal composite endpoint of CV death, nonfatal MI or non-fatal stroke.

Figure thirteen – Time to First Occurrence of CV death, MI or Stroke (PEGASUS)

Ti = Ticagrelor BID, CI = Confidence interval; HR = Take a chance ratio; KM = Kaplan-Meier; Northward = Number of patients.

Both the 60 mg and 90 mg regimens of BRILINTA in combination with aspirin were superior to aspirin alone in reducing the incidence of CV death, MI or stroke. The absolute risk reductions for BRILINTA plus aspirin vs. aspirin alone were 1.27% and 1.19% for the lx and 90 mg regimens, respectively. Although the efficacy profiles of the two regimens were similar, the lower dose had lower risks of bleeding and dyspnea.

Table 8 shows the results for the 60 mg plus aspirin regimen vs. aspirin alone.

Table viii – Incidences of the primary blended endpoint, master composite endpoint components, and secondary endpoints (PEGASUS)

	BRILINTA* N=7045	Placebo N=7067	HR (95% CI)	p-value
	Events / one thousand patient years	Events / 1000 patient years
Time to first CV death, MI, or stroke†	26	31	0.84 (0.74, 0.95)	0.0043
CV Death‡,§	nine	eleven	0.83 (0.68, one.01)
Myocardial infarction§	15	eighteen	0.84 (0.72, 0.98)
Stroke§	5	7	0.75 (0.57, 0.98)
All-cause mortality‡	16	18	0.89 (0.76, one.04)
CI = Confidence interval; CV = Cardiovascular; HR = Risk ratio; MI = Myocardial infarction; N = Number of patients. *lx mg BID † Primary composite endpoint ‡ Secondary endpoints § The result rate for the components CV death, MI and stroke are calculated from the actual number of first events for each component.

In PEGASUS, the relative risk reduction (RRR) for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (xvi% RRR) were similar.

The treatment effect of BRILINTA 60 mg over aspirin appeared like across about pre-defined subgroups, see Figure xiv.

Figure 14 – Subgroup analyses of ticagrelor 60 mg (PEGASUS)

Notation: The effigy above presents effects in diverse subgroups all of which are baseline characteristics and most of which were pre-specified. The 95% confidence limits that are shown exercise not take into business relationship how many comparisons were made, nor exercise they reflect the effect of a particular factor after adjustment for all other factors. Credible homogeneity or heterogeneity among groups should not be over-interpreted.

Coronary Avenue Affliction Just No Prior Stroke Or Myocardial Infarction

THEMIS

The THEMIS study (NCT01991795) was a double-blind, parallel group, written report in which 19,220 patients with CAD and Type 2 Diabetes Mellitus (T2DM) only no history of MI or stroke were randomized to twice daily BRILINTA or placebo, on a groundwork of 75-150 mg of aspirin. The main endpoint was the composite of start occurrence of CV expiry, MI, and stroke. CV death, MI, ischemic stroke, and all-cause death were assessed equally secondary endpoints.

Patients were eligible to participate if they were ≥ 50 years quondam with CAD, defined equally a history of PCI or CABG, or angiographic evidence of ≥ 50% lumen stenosis of at least 1 coronary avenue and T2DM treated for at least 6 months with glucose-lowering medication. Patients with previous intracerebral hemorrhage, gastrointestinal bleeding within the past 6 months, known bleeding diathesis, and coagulation disorder were excluded. Patients taking anticoagulants or ADP receptor antagonists were excluded from participating, and patients who developed an indication for those medications during the trial were discontinued from study drug.

Patients were treated for a median of 33 months and up to 58 months.

Patients were predominantly male (69%) with a hateful age of 66 years. At baseline, lxxx% had a history of coronary artery revascularization; 58% had undergone PCI, 29% had undergone a CABG and 7% had undergone both. The proportion of patients studied in the US was 12%. Patients in THEMIS had established CAD and other adventure factors that put them at higher cardiovascular hazard.

BRILINTA was superior to placebo in reducing the incidence of CV expiry, MI, or stroke. The effect on the composite endpoint was driven past the private components MI and stroke; meet Table 9.

Table ix – Primary composite endpoint, principal endpoint components, and secondary endpoints (THEMIS)

	BRILINTA N=9619	Placebo Northward=9601	HR (95% CI)	p-value
	Events / 1000 patient years	Events / 1000 patient years
Fourth dimension to first CV death, MI, or stroke*	24	27	0.90 (0.81, 0.99)	0.04
CV death†	12	11	1.02 (0.88, 1.xviii)
Myocardial infarction†	nine	11	0.84 (0.71, 0.98)
Stroke†	6	seven	0.82 (0.67, 0.99)
Secondary endpoints
CV expiry	12	11	1.02 (0.88, 1.18)
Myocardial infarction	9	xi	0.84 (0.71, 0.98)
Ischemic stroke	5	6	0.80 (0.64, 0.99)
All-cause death	18	19	0.98 (0.87, 1.10)
CI = Confidence interval; CV = Cardiovascular; 60 minutes = Take a chance ratio; MI = Myocardial infarction. * Primary endpoint † The outcome rate for the components CV death, MI and stroke are calculated from the actual number of commencement events for each component.

The Kaplan-Meier curve (Effigy 15) shows time to first occurrence of the master blended endpoint of CV death, MI, or stroke.

Effigy 15 - Fourth dimension to First Occurrence of CV death, MI or Stroke (THEMIS)

T = Ticagrelor; P = Placebo; N = Number of patients.

The treatment result of BRILINTA appeared similar beyond patient subgroups, see Effigy 16.

Effigy 16 –Subgroup analyses of ticagrelor (THEMIS)

Annotation: The effigy above presents effects in various subgroups all of which are baseline characteristics. The 95% confidence limits that are shown do non take into account how many comparisons were made, nor practice they reflect the consequence of a particular factor after adjustment for all other factors. Credible homogeneity or heterogeneity among groups should not exist over-interpreted.

Acute Ischemic Stroke Or Transient Ischemic Attack (TIA)

THALES

The THALES study (NCT03354429) was a 11016-patient, randomized, double-blind, parallel-group study of BRILINTA 90 mg twice daily versus placebo in patients with acute ischemic stroke or transient ischemic assault (TIA). The main endpoint was the showtime occurrence of the composite of stroke and expiry up to xxx days. Ischemic stroke was assessed equally i of the secondary endpoints.

Patients were eligible to participate if they were ≥twoscore years old, with non-cardioembolic acute ischemic stroke (NIHSS score ≤v) or high-run a risk TIA (divers every bit ABCD² score ≥six or ipsilateral atherosclerotic stenosis ≥50% in the internal carotid or an intracranial artery). Patients who received thrombolysis or thrombectomy inside 24 hours prior to randomization were not eligible.

Patients were randomized inside 24 hours of onset of an astute ischemic stroke or TIA to receive 30 days of either BRILINTA (ninety mg twice daily, with an initial loading dose of 180 mg) or placebo, on a background of aspirin initially 300-325 mg then 75-100 mg daily. The median treatment duration was 31 days.

BRILINTA was superior to placebo in reducing the rate of the chief endpoint (blended of stroke and death), respective to a relative take a chance reduction (RRR) of 17% and an absolute gamble reduction (ARR) of 1.ane% (Table 10). The effect was driven primarily by a significant reduction in the stroke component of the main endpoint (19% RRR, 1.one% ARR).

Tabular array 10 - Incidences of the primary composite endpoint, main blended endpoint components, and secondary endpoint (THALES)

	BRILINTA N=5523		Placebo N=5493		HR (95% CI)	p-value
	northward (patients with event)	KM%	n (patients with effect)	KM%
Time to first Stroke or Death	303	5.4%	362	6.5%	0.83 (0.71, 0.96)	0.015
Time to first Stroke*	284	5.1%	347	6.3%	0.81 (0.69, 0.95)
Time to Death*	36	0.6%	27	0.5%	1.33 (0.81, two.nineteen)
Secondary Endpoint
Time to start Ischemic Stroke	276	5.0%	345	6.2%	0.79 (0.68, 0.93)	0.004
CI = Confidence interval; Hour = Hazard ratio; KM = Kaplan-Meier percentage calculated at 30 days; North = Number of patients *The number of patients with the consequence of interest. In the time to first stroke, patients who died are censored at the fourth dimension of death.

The Kaplan-Meier curve (Figure 17) shows the fourth dimension to offset occurrence of the primary composite endpoint of stroke and decease.

Figure 17 – Time to First Occurrence of Stroke or Death (THALES)

KM%: Kaplan-Meier percent evaluated at Day xxx; T=Ticagrelor; P=placebo; N=Number of patients

BRILINTA's treatment effect on stroke and on decease accrued over the first 10 days and was sustained at thirty days.

Although not studied, this suggests that shorter handling could result in similar benefit and reduced bleeding risk.

The handling effect of BRILINTA was generally consequent across pre-defined subgroups (Figure 18).

Figure 18 – Subgroup analyses of ticagrelor ninety mg (THALES)

Note: The figure above presents furnishings in diverse subgroups all of which are baseline characteristics and were pre-specified. The 95% conviction limits that are shown practise not take into business relationship how many comparisons were fabricated, nor exercise they reflect the outcome of a particular factor after aligning for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

At Solar day 30, there was an absolute reduction of one.2% (95% CI: -two.1%, -0.three%) in the incidence of not-hemorrhagic stroke and death (excluding fatal bleed) favoring ticagrelor (294 events: 5.3%) over placebo (359 events: half dozen.five%) in the intention- to-treat population. In the same population, in that location was an absolute increase of 0.4% (95% CI: 0.2%, 0.half dozen%) in the incidence of GUSTO severe bleeding unfavorable to ticagrelor arm (28 events: 0.v%) compared to the placebo arm (7 events: 0.1%).

PATIENT Data

BRILINTA^®
(brih-LIN-tah)
(ticagrelor) Tablets

What is the most important information I should know about BRILINTA?

BRILINTA is used to lower your run a risk of having, or dying from, a heart attack or stroke. BRILINTA (and similar drugs) tin can crusade bleeding that tin be serious and sometimes lead to death. In cases of serious bleeding, such as internal bleeding, the bleeding may event in the need for blood transfusions or surgery. While you accept BRILINTA:

• you may bruise and drain more hands
• you are more likely to have olfactory organ bleeds
• information technology will take longer than usual for any bleeding to stop

Call your doctor correct abroad, if you have any of these signs or symptoms of bleeding while taking BRILINTA:

• haemorrhage that is severe or that you cannot command
• pink, cherry-red or brownish urine
• vomiting claret or your vomit looks like "coffee grounds"
• ruby or blackness stools (looks like tar)
• coughing upwardly blood or blood clots

Exercise 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 gamble of getting a blood clot in the stent, having a heart attack, or dying. If yous end 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 v days before surgery. This will help to decrease your risk of bleeding with your surgery or procedure. Your dr. 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 virtually the dose of aspirin that you should take with BRILINTA. In most cases, yous should non have a dose of aspirin higher than 100 mg daily because it tin can affect how well BRILINTA works. Practise not take doses of aspirin college than what your doc tells yous to accept. Tell your dr. if you take other medicines that contain aspirin, and practise non take new over-the-counter medicines with aspirin in them.

What is BRILINTA?

BRILINTA is a prescription medicine used to:

• decrease your risk of death, heart attack, and stroke in people with a blockage of claret flow to the eye (acute coronary syndrome or ACS) or a history of a heart attack. BRILINTA can likewise decrease your risk of blood clots in your stent in people who have received stents for the treatment of ACS.
• decrease your risk of a showtime heart assail or stroke in people who have a condition where the claret flow to the middle is decreased (coronary avenue disease or CAD) who are at high risk for having a middle assault or stroke.
• subtract your risk of stroke in people who are having a stroke (acute ischemic stroke) or mini-stroke (transient ischemic attack or TIA).

It is not known if BRILINTA is safe and effective in children.

Do not take BRILINTA if y'all:

• accept a history of bleeding in the encephalon
• are bleeding at present
• are allergic to ticagrelor or whatsoever of the ingredients in BRILINTA. See the end of this Medication Guide for a consummate list of ingredients in BRILINTA.

Before taking BRILINTA, tell your md about all of your medical conditions, if you:

• accept had bleeding issues in the by
• have had any recent serious injury or surgery
• program to have surgery or a dental procedure
• have a history of breadbasket ulcers or colon polyps
• have lung problems, such as COPD or asthma
• take liver problems
• have a history of stroke
• are pregnant or programme to get pregnant. It is not known if BRILINTA will harm your unborn baby. You and your doctor should make up one's mind if yous volition take BRILINTA.
• are breastfeeding or plan to breastfeed. It is not known if BRILINTA passes into your breast milk. Y'all and your medico should decide if you will have BRILINTA or breastfeed. You should not exercise both without talking with your doctor.

Tell all of your doctors and dentists that you are taking BRILINTA. They should talk to the physician who prescribed BRILINTA for you before yous have any surgery or invasive process.

Tell your doctor well-nigh all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. BRILINTA may impact the fashion other medicines work, and other medicines may affect how BRILINTA works.

Specially tell your md if y'all take:

• an HIV-AIDS medicine
• medicine for heart conditions or loftier blood pressure
• medicine for high blood cholesterol levels
• medicine used to control pain
• an anti-fungal medicine by oral cavity
• an antibiotic medicine
• an anti-seizure medicine
• a blood thinner medicine
• rifampin

Ask your medico or pharmacist if you are non sure if your medicine is listed to a higher place.

Know the medicines y'all accept. Go on a listing of them to show your dr. and chemist when you get a new medicine.

How should I take BRILINTA?

• Take BRILINTA exactly every bit prescribed past your doctor.
• Your doctor will tell you how many BRILINTA tablets to take and when to take them.
• Take BRILINTA with aspirin as directed by your md.
• Yous may accept BRILINTA with or without food.
• Take your doses of BRILINTA around the aforementioned time every day.
• If y'all forget to take your scheduled dose of BRILINTA, take your next dose at its scheduled fourth dimension. Do not take 2 doses at the aforementioned time unless your doctor tells you to.
• If you lot take too much BRILINTA or overdose, call your doctor or toxicant control center correct away, or go to the nearest emergency room.
• If yous are unable to swallow the tablet(southward) whole, you may shell the BRILINTA tablet(s) and mix information technology with water. Drink all the water right abroad. Refill the drinking glass with water, stir, and drink all the water.

What are the possible side effects of BRILINTA?

BRILINTA can cause serious side effects, including:

• Come across "What is the most of import information I should know almost BRILINTA?"
• Shortness of breath. Call your doctor if you take new or unexpected shortness of jiff when you are at residual, at night, or when y'all are doing whatsoever activity. Your doc can determine what treatment is needed.

These are not all of the possible side effects of BRILINTA.

Call your doctor for medical advice about side furnishings. Y'all may study side effects to FDA at 1-800-FDA-1088.

How should I store BRILINTA?

• Store BRILINTA at room temperature betwixt 68°F to 77°F (20°C to 25°C).

Keep BRILINTA and all medicines out of the achieve of children.

Full general information most the safe and effective apply of BRILINTA.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Practise not use BRILINTA for a condition for which it was not prescribed. Exercise not give BRILINTA to other people, even if they have the same symptoms you have. It may harm them. Yous tin can ask your pharmacist or physician for data nigh BRILINTA that is written for wellness professionals.

What are the ingredients in BRILINTA?

Active ingredient: ticagrelor.

90 mg tablets:

Inactive ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellowish.

60 mg tablets:

Inactive 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 carmine.

This Medication Guide has been approved past the U.Southward. Food and Drug Administration.

From

Report Problems to the Food and Drug Administration

You are encouraged to written report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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Source: https://www.rxlist.com/brilinta-drug.htm

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