ticagrelor (Rx)

Brand and Other Names:Brilinta
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 60mg
  • 90mg

Acute Coronary Syndrome or History of MI

Indicated to reduce risk of cardiovascular death, MI, and stroke in patients with acute coronary syndrome (ACS) or history of MI

Also, reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS

For at least the first 12 months following ACS, it is superior to clopidogrel to lower risk of further major adverse cardiovascular events (MACE) (PLATO study)

Loading dose (following ACS event): 180 mg PO x 1 dose

Maintenance dose (for first year following ACS event): 90 mg PO BID

Maintenance dose (after 1 year of maintenance): 60 mg PO BID

Administer with daily maintenance dose of aspirin 75-100 mg; the use of aspirin above 100 mg decreases effectiveness of ticagrelor

Coronary Artery Disease

Indicated to reduce risk of a first MI or stroke in patients with coronary artery disease (CAD) who are at high risk for such events

While use is not limited to this setting, efficacy was established in patients with type 2 diabetes mellitus (T2DM)

CAD, but no prior stroke or MI: 60 mg PO BID

Administer with daily maintenance dose of aspirin 75-100 mg

For all patients with ACS, use that specific dosing instead

Acute Ischemic Stroke or TIA

Indicated to reduce risk of stroke in patients with acute ischemic stroke (NIH stroke scale score ≤5) or high-risk transient ischemic attack (TIA)

Loading dose: 180 mg PO x 1 dose

Maintenance dose: 90 mg PO BID for up to 30 days

Use with loading dose of aspirin (300-325 mg) and daily maintenance dose of 75-100 mg

Dosage Modifications

Renal impairment

  • No dosage adjustment needed
  • End-stage renal disease
    • Clinical efficacy and safety studies did not enroll patients with end-stage renal disease (ESRD) on dialysis
    • 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

Hepatic impairment

  • Mild: No dose adjustment required
  • Moderate: Data are limited; caution advised
  • Severe: Not studied; avoid use due to likely increase systemic exposure to ticagrelor

Safety and efficacy not established

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Interactions

Interaction Checker

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            Adverse Effects

            >10%

            Dyspnea (13.8%)

            Bleeding (see specific data listed below)

            1-10%

            Dizziness (4.5%)

            Nausea (4.3%)

            Diarrhea (3.7%)

            Ventricular pauses (6%)

            Bleeding

            Non-CABG related bleeds (PLATO trial)

            • Total bleeds (major + minor) (7.7%)
            • Major bleeds
              • Major bleeds (3.9%)
              • Fatal/life-threatening (1.9%)
              • Fatal (0.2%)
              • Intracranial (fatal/life-threatening) (0.3%)

            CABG related bleeds (PLATO trial)

            • Total major bleeds (81.3%)
            • Major bleeds when antiplatelet therapy stopped 5 days before CABG (75%)
            • Fatal/life-threatening (43.8%)
            • Fatal (0.8%)

            Bleeding events (PEGASUS trial)

            • TIMI major
              • TIMI major: 8 per 1000 patient years
              • Fatal: 1 per 1000 patient years
              • Intracranial hemorrhage: 2 per 1000 patient years
            • TIMI major or minor
              • 11 per 1000 patient years

            Bleeding events (THEMIS trial)

            • TIMI major: 9 per 1000 patient years
            • TIMI major or minor: 12 per 1000 patient years
            • TIMI major or minor or requiring medical attention: 46 per 1000 patient years
            • Fatal bleeding: 1 per 1000 patient years
            • Intracranial hemorrhage: 3 per 1000 patient years

            Postmarketing Reports

            Immune system disorders: Hypersensitivity reactions including angioedema

            Skin and subcutaneous tissue disorders: Rash

            Blood and lymphatic system disorders: Thrombotic thrombocytopenic purpura (rare)

            Respiratory disorders: Central sleep apnea, Cheyne-Stokes respiration

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            Warnings

            Black Box Warnings

            Bleeding risk

            • Like other antiplatelet agents, can cause significant, sometimes fatal, bleeding
            • Do not use with active pathological bleeding or a history of intracranial hemorrhage
            • Do not start in patients planned to undergo urgent coronary artery bypass graft surgery (CABG); when possible, discontinue 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 surgical procedures after starting ticagrelor
            • If possible, manage bleeding without discontinuing; stopping ticagrelor increases risk of subsequent cardiovascular events

            Aspirin dose and ticagrelor effectiveness

            • Aspirin maintenance dose >100 mg reduces the effectiveness of ticagrelor and should be avoided
            • After any initial loading dose, use with aspirin 75-100 mg/day

            Contraindications

            Hypersensitivity (eg, angioedema)

            History of intracranial hemorrhage (ICH)

            Active pathologic bleeding (eg, peptic ulcer, ICH)

            Cautions

            Inhibits platelet function, and thereby, increases bleeding risk; if possible, manage bleeding without discontinuing drug; stopping ticagrelor increases risk of subsequent cardiovascular events

            Discontinuation of therapy will increase risk of myocardial infarction, stroke, and death in patients being treated for coronary artery disease; if drug must be temporarily discontinued (eg, to treat bleeding or for significant surgery), restart it as soon as possible; when possible, interrupt therapy for five days prior to surgery that has a major risk of bleeding and resume therapy as soon as hemostasis is achieved

            Surgery: When possible, discontinue 5 days prior to surgery

            Dyspnea reported; intensity described as usually mild-to-moderate and decreases/resolves during continued treatment; if dyspnea symptoms intolerable consider administering a different antiplatelet agent

            Can cause ventricular pauses; bradyarrhythmias, including AV block reported; patients with history of sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardia-related syncope who were not protected by a pacemaker were excluded from PLATO and PEGASUS and may be at increased risk of developing bradyarrhythmias with ticagrelor

            Avoid use with severe hepatic impairment, which may increase ticagrelor serum levels

            Reported to cause false negative results in platelet functional tests (eg, HIPA assay for HIT)

            Drug interaction overview

            • Ticagrelor is a CYP3A4 substrate and weak CYP3A4 inhibitor
            • May cause false negative results in platelet functional tests (to include, but may not be limited to, the heparin-induced platelet aggregation [HIPA] assay) for patients with heparin-induced thrombocytopenia (HIT)
            • Simvastatin or lovastatin
              • Ticagrelor increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4
              • Avoid simvastatin and lovastatin doses >40 mg
            • Digoxin
              • Ticagrelor inhibits the P-glycoprotein transporter
              • Monitor digoxin levels with initiation of, or change in ticagrelor dose
            • Opioids
              • As with other oral P2Y12 inhibitors, coadministration of opioid agonists delay and reduce the absorption of ticagrelor and its active metabolite presumably because of slowed gastric emptying
              • Consider the use of a parenteral antiplatelet agent in ACS patients requiring coadministration of morphine or other opioid agonists
            • Strong CYP3A4 inhibitors
              • Avoid coadministration
              • Strong CYP3A inhibitors substantially increase ticagrelor exposure and therefore increase the risk of adverse effects (eg, dyspnea, bleeding)
            • Strong CYP3A4 inducers
              • Avoid coadministration
              • Strong CYP3A inducers substantially reduce ticagrelor exposure and efficacy
            • Aspirin
              • Aspirin maintenance doses >100 mg/day reduces ticagrelor efficacy
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            Pregnancy & Lactation

            Pregnancy

            Available data from case reports on use in pregnant females have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

            Animal data

            • Drug given to pregnant rats and pregnant rabbits during organogenesis caused structural abnormalities in the offspring at maternal doses about 5 to 7 times maximum recommended human dose (MRHD) based on body surface area; when given to rats during late gestation and lactation, pup death and effects on pup growth were seen at ~10 times the MRHD

            Lactation

            There are no data on presence of drug or metabolites in human milk, effect on breastfed infants, or 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 therapy

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            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

            Patients can be transitioned from clopidogrel to ticagrelor without interruption of antiplatelet effect

            Inhibition of platelet aggregation (IPA)

            • Transitioning from clopidogrel to ticagrelor resulted in an absolute IPA increase of 26.4%
            • Transitioning from ticagrelor to clopidogrel an absolute IPA decrease of 24.5%

            Absorption

            Bioavailability: 36%

            Peak plasma time

            Tablets: 1.5 hr (ticagrelor); 2.5 hr (AR-C124910XX [active])

            Crushed tables administered via NG tube: 1 hr (ticagrelor); 2 hr (AR-C124910XX [active])

            Distribution

            Vd (steady-state): 88 L

            Protein bound: >99% (ticagrelor and active metabolite)

            Metabolism

            Metabolized primaryly by CYP3A4 to form major active metabolite (AR-C124910XX); metabolized by CYP3A5 to a lesser extent

            Systemic exposure to AR-C124910XX accounts for ~30-40%

            Ticagrelor and its major active metabolite are weak P-gp substrates and inhibitors

            Elimination

            Half-life: 7 hr (ticagrelor); 9 hr (active metabolite)

            Excretion

            • Ticagrelor: Feces (58%); urine (26%)
            • Active metabolite: Primarily by biliary excretion; urine (<1%)
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            Administration

            Oral Administration

            Do not administer with another oral P2Y12 platelet inhibitor

            May administer with or without food

            Missed dose: Skip missed dose and take next dose at its scheduled time; do not take 2 doses at the same time

            Unable to swallow tablet whole

            • Crush tablets, mix with water, and drink immediately
            • Refill glass with water, stir, and drink contents to ensure complete dose is consumed
            • May be administered via nasogastric (NG) tube (≥CH8)
            • Important to flush NG tube through with water after administration of the mixture

            Storage

            Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.