ticagrelor (Rx)

>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

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)

Central sleep apnea (CSA) including Cheyne-Stokes respiration (CSR) reported in post-marketing setting, including recurrence or worsening of CSA/CSR following rechallenge; if central sleep apnea suspected, consider further clinical assessment

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

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.

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%)

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)