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, 2 nd 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

CYP3A4/5 substrate

• Metabolized by CYP3A4/5
• Avoid coadministration with strong CYP3A inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)
• Avoid coadministration with potent CYP3A inducers (eg, rifampin, dexamethasone, phenytoin, carbamazepine, phenobarbital)

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%

Pharmacokinetics

Bioavailability: 36%

Peak Plasma Time: 1.5 hr; 2.5 hr (active metabolite)

Protein Bound: >99% (including active metabolite)

Vd: 88 L

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

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

Excretion (ticagrelor): feces (58%); urine (26%)

Excretion (active metabolite): Primarily by biliary excretion; urine (<1%)

Oral Administration

If patient has received a loading dose of clopidogrel, may be started on ticagrelor

May administer with or without food

If dose is missed, instruct patient to take one tablet (their next dose) at its scheduled time

Unable to swallow tablet whole

For patients who are unable to swallow the tablet(s) whole, tablets can be crushed, mixed with water, and drunk immediately

The glass should be refilled with water, stirred and the contents drunk to ensure the complete dose is consumed

The mixture can also be administered via a nasogastric tube (≥CH8)

It is important to flush the nasogastric tube through with water after administration of the mixture