ticagrelor (Rx)

>10%

Dyspnea (13.8%)

Bleeding (see specific data listed below)

1-10%

Headache (6.5%)

Cough (4.9%)

Dizziness (4.5%)

Nausea (4.3%)

Atrial fibrillation (4.2%)

Hypertension (3.8%)

Noncardiac chest pain (3.7%)

Diarrhea (3.7%)

Back pain (3.6%)

Hypotension (3.2%)

Fatigue (3.2%)

Chest pain (3.1%)

Syncope (1.7%)

<1%

Dyspena (0.9%)

Bleeding

Non-CABG related bleeds

• Total bleeds (major + minor) (8.7%)
• Major bleeds (4.5%)
• Fatal/life-threatening (2.1%)
• Fatal (0.2%)
• Intracranial (fatal/life-threatening) (0.3%)

CABG related bleeds

• Total major bleeds (85.8%)
• Major bleeds when antiplatelet therapy stopped 5 days before CABG (75%)
• Fatal/life-threatening (48.1%)
• Fatal (0.9%)

Postmarketing Reports

Immune system disorders: Hypersensitivity reactions including angioedema (see Contraindications)

Skin and subcutaneous tissue disorders: Rash

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

Contraindications

Hypersensitivity (eg, angioedema)

History of intracranial hemorrhage (ICH)

Active pathologic bleeding (eg, peptic ulcer, ICH)

Cautions

Drugs that inhibit platelet function, including ticagrelor, increase bleeding risk; if possible, manage bleeding without discontinuing drug; stopping ticagrelor increases the risk of subsequent cardiovascular events

Avoid interruption of treatment; if ticagrelor must be temporarily discontinued (eg, to treat bleeding or for elective surgery), restart as soon as possible; discontinuation will increase the risk of myocardial infarction, stent thrombosis, and death

Surgery: When possible, discontinue 5 days prior to surgery

Aspirin maintenance doses >100 mg decrease ticagrelor effectiveness; therefore, after initial aspirin loading dose (usually 325 mg), use with aspirin maintenance dose of 75-100 mg/day (see Black Box Warnings)

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

Ticagrelor can cause ventricular pauses

Bradyarrhythmias including AV block have been reported in the post- Marketing setting; Patients with a history of sick sinus syndrome, 2nd or 3rd degree AV block or bradycardia-related syncope 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 is likely to increase ticagrelor serum levels

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 women 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, effects on breastfed infant, 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

Peak plasma time: 1.5 hr (ticagrelor); 2.5 hr (AR-C124910XX [active])

Bioavailability: 36%

Distribution

Vd (steady-state): 88 L

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

Metabolism

Metabolized by: CYP3A4 is the major enzyme responsible for formation of its major active metabolite (AR-C124910XX); metabolized by CYP3A5 to a lesser extent

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

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

Elimination

Half-life elimination: 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

Unable to swallow tablet whole

• Tablets can be crushed, mixed with water, and drunk 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)