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Ticagrelor

Pronunciation

Pronunciation

(tye KA grel or)

Index Terms

  • AZD6140

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Brilinta: 60 mg, 90 mg

Brand Names: U.S.

  • Brilinta

Pharmacologic Category

  • Antiplatelet Agent
  • Antiplatelet Agent, Cyclopentyltriazolopyrimidine

Pharmacology

Reversibly and noncompetitively binds the adenosine diphosphate (ADP) P2Y12 receptor on the platelet surface which prevents ADP-mediated activation of the GPIIb/IIIa receptor complex thereby reducing platelet aggregation. Due to the reversible antagonism of the P2Y12 receptor, recovery of platelet function is likely to depend on serum concentrations of ticagrelor and its active metabolite.

Absorption

Rapid

Distribution

88 L

Metabolism

Hepatic via CYP3A4/5 to active metabolite (AR-C124910XX)

Excretion

Feces (58%); urine (26%); actual amount of parent drug and active metabolite excreted in urine was <1% of total dose administered.

Onset of Action

Inhibition of platelet aggregation (IPA): 180 mg loading dose: ~41% within 30 minutes (similar to clopidogrel 600 mg at 8 hours); Peak effect: Time to maximal IPA: 180 mg loading dose: IPA ~88% at 2 hours post administration

Time to Peak

Whole tablets: Parent drug: 1.5 hours (median; range: 1 to 4 hours); Active metabolite (AR-C124910XX): 2.5 hours (median; range: 1.5 to 5 hours)

Crushed tablets: Oral or nasogastric tube administration: Parent drug: ~1 hour (median; range: 1 to 4 hours); Active metabolite (AR-C124910XX): 2 hours (median; range: 1 to 8 hours). Note: Significantly higher concentrations of both ticagrelor and AR-C124910XX may appear at earlier time points (0.5 and 1 hour, respectively) when administered as crushed tablets (Teng 2015).

Duration of Action

IPA: 180 mg loading dose: 87% to 89% maintained from 2 to 8 hours; 24 hours after the last maintenance dose, IPA is 58% (similar to maintenance clopidogrel)

Time after discontinuation when IPA is 30%: ~56 hours; IPA 10%: ~110 hours (Gurbel, 2009). Mean IPA observed with ticagrelor at 3 days post-discontinuation was comparable to that observed with clopidogrel at 5 days post discontinuation.

Half-Life Elimination

Parent drug: ~7 hours; active metabolite: ~9 hours

Protein Binding

>99% (parent drug and active metabolite)

Special Populations: Renal Function Impairment

Effects of renal impairment on the pharmacokinetics are modest and do not require dose adjustment. Patients receiving dialysis have not been studied.

Special Populations: Hepatic Function Impairment

Effects of mild hepatic impairment on the pharmacokinetics are modest and do not require dose adjustment. Not studied in patients with moderate or severe hepatic impairment.

Special Populations: Elderly

Effects of age on the pharmacokinetics are modest and do not require dose adjustment.

Special Populations: Gender

Effects of gender on the pharmacokinetics are modest and do not require dose adjustment.

Special Populations: Race

Effects of race (white or Japanese) on the pharmacokinetics are modest and do not require dose adjustment.

Special Populations Note

Smoking

Mean Cl was increased by approximately 22% in smokers; no dose adjustment is necessary.

Use: Labeled Indications

Acute coronary syndrome: Reduction of the rate of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. Ticagrelor also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.

Use: Unlabeled

In patients with allergy or major gastrointestinal intolerance to aspirin, initial treatment of UA/NSTEMI; Note: Dual antiplatelet therapy with another P2Y12 receptor inhibitor is not recommended in this situation (ACCF/AHA [Anderson, 2013]).

Contraindications

Hypersensitivity (eg, angioedema) to ticagrelor or any component of the formulation; active pathological bleeding (eg, peptic ulcer or intracranial hemorrhage); history of intracranial hemorrhage

Canadian labeling: Additional contraindications (not in US labeling): Moderate to severe hepatic impairment; concomitant use of strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, ritonavir, atazanavir, nefazodone)

Dosage

Oral, NG: Adults:

Acute coronary syndrome: Unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI), ST-segment elevation myocardial infarction (STEMI): Initial: 180 mg loading dose (with a loading dose of aspirin [eg, 325 mg] if not already receiving); Maintenance: 90 mg twice daily; initiated 12 hours after initial loading dose with low-dose aspirin 75 to 100 mg/day (US labeling) or 75 to 150 mg/day (Canadian labeling) or 81 mg/day indefinitely in patients with UA/NSTEMI or STEMI as recommended by ACCF/AHA/SCAI). Continue initial therapy with ticagrelor for 12 months. After 12 months of initial therapy, reduce ticagrelor dose to 60 mg twice daily. Patients in the clinical trial were followed up over a period of ~3 years (Bonaca, 2015).

Duration of ticagrelor (in combination with aspirin) after stent placement: Premature interruption of therapy may result in stent thrombosis with subsequent fatal and nonfatal MI. According to the ACCF/AHA/SCAI PCI guidelines, in patients with ACS receiving either stent type (bare metal [BMS] or drug-eluting stent [DES]) or those receiving a DES for a non-ACS indication, ticagrelor for at least 12 months is recommended (ACCF/AHA/SCAI [Levine, 2011]). The ACCF/AHA guidelines for the management of UA/NSTEMI recommend up to 12 months of ticagrelor in patients with ACS who receive a BMS (ACCF/AHA [Anderson, 2013]). A duration >12 months may be considered in patients with DES placement. After 12 months of initial therapy, the manufacturer recommends reducing the dose of ticagrelor to 60 mg twice daily. Recent data have demonstrated that continued dual antiplatelet therapy (ticagrelor not included in clinical trial) for a total of 30 months (compared to 12 months) significantly reduced the risk of stent thrombosis and major adverse cardiovascular/cerebrovascular events but was associated with a higher risk of bleeding (Mauri, 2014). Patients receiving a BMS for a non-ACS indication should be given ticagrelor for at least 1 month and ideally up to 12 months; if patient is at increased risk of bleeding, give for a minimum of 2 weeks (ACCF/AHA/SCAI [Levine, 2011]).

Conversion from clopidogrel to ticagrelor: May initiate ticagrelor 90 mg twice daily beginning 24 hours after last clopidogrel dose (loading or maintenance). Patients who are in the acute phase of an acute coronary syndrome, especially if determined to be clopidogrel nonresponsive, may be considered for administration of ticagrelor 180 mg loading dose followed by 90 mg twice daily regardless of previous clopidogrel exposure, taking into consideration the administration of other antiplatelet agents (eg, GP IIb/IIIa inhibitors) (Gurbel, 2010; Wallentin, 2009). In one single blinded study, patients with ACS receiving ongoing clopidogrel treatment who were converted to ticagrelor without a loading dose did not experience a reduction in platelet inhibition compared to those who received a loading dose of ticagrelor (Caiazzo, 2014). Note: In general, conversion to ticagrelor results in an absolute inhibition of platelet aggregation (IPA) increase of 26.4%.

Dosage adjustment in renal impairment: No dosage adjustment necessary.

Hemodialysis: No dosage adjustments provided by the manufacturer; however, ticagrelor is not renally eliminated. Ticagrelor is not expected to be dialyzable.

Dosage adjustment in hepatic impairment:

US labeling:

Mild impairment: No dosage adjustment necessary.

Moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, undergoes hepatic metabolism; use caution.

Severe impairment: Avoid use.

Canadian labeling:

Mild impairment: No dosage adjustment necessary.

Moderate or severe impairment: Use is contraindicated.

Extemporaneously Prepared

A suspension for oral administration may be prepared by crushing one or two 90 mg tablets in a mortar (for 60 seconds) and placing in a dosing cup. To ensure the full dose is received, rinse mortar with 100 mL purified water, transfer to dosing cup, and repeat rinse (Crean, 2013; Parodi, 2015).

A suspension for NG tube administration may be prepared by crushing one or two 90 mg tablets in a mortar (for 60 seconds); add 50 mL purified water to mortar and stir (for 60 seconds); transfer the suspension to a 50 mL oral enteral syringe and administer via NG tube. To ensure the full dose is received, add another 50 mL purified water to the mortar and stir for 60 seconds; using the same 50 mL oral enteral syringe, withdraw the suspension and administer entire amount via NG tube (Crean, 2013).

When stored in a PVC oral syringe for up to 2 hours, there was no degradation of the suspension detected (Crean, 2013).

Administration

May be administered without regard to meals. Missed doses should be taken at their next regularly scheduled time. For patients unable to swallow whole, tablets may be crushed and mixed with water to create a suspension for oral or NG (CH8/Fr8 or greater according to the manufacturer) use. If suspension is administered orally, refill glass with water, stir and drink; if administered via NG tube, flush NG tube through with water after administration (Crean, 2013; Parodi, 2015). Administration of crushed tablets, while bioequivalent to administration of whole tablets, may result in increased concentrations of ticagrelor and the major active metabolite at earlier time points (Teng 2015).

Dietary Considerations

May be taken without regard to meals.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Apixaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Aspirin: May enhance the antiplatelet effect of Ticagrelor. Aspirin may diminish the therapeutic effect of Ticagrelor. More specifically, the benefits of ticagrelor relative to clopidogrel may be diminished in adult patients receiving daily aspirin doses greater than 100-150 mg daily. Management: Avoid daily aspirin doses greater than 100 mg in adults receiving ticagrelor. Canadian recommendations are to avoid adult daily aspirin doses greater than 150 mg. Daily low-dose aspirin (U.S.: 75-100 mg; Canada: 75-150 mg) is recommended. Consider therapy modification

AtorvaSTATin: Ticagrelor may increase the serum concentration of AtorvaSTATin. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

CycloSPORINE (Systemic): May increase the serum concentration of Ticagrelor. Monitor therapy

CYP2C9 Substrates: CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ticagrelor. Avoid combination

CYP3A4 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor. Avoid combination

Dabigatran Etexilate: Ticagrelor may enhance the anticoagulant effect of Dabigatran Etexilate. Ticagrelor may increase the serum concentration of Dabigatran Etexilate. Management: Monitor closely for signs and symptoms of bleeding if dabigatran is used in combination with ticagrelor. Canadian product labeling recommends avoiding the concomitant use of these agents while US labeling makes no such recommendation. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Dexamethasone (Systemic): May decrease serum concentrations of the active metabolite(s) of Ticagrelor. Dexamethasone (Systemic) may decrease the serum concentration of Ticagrelor. Avoid combination

Digoxin: Ticagrelor may increase the serum concentration of Digoxin. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Edoxaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider the anticipated risks and benefits of this combination. If combined, increased monitoring for bleeding is recommended. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Grapefruit Juice: May increase the serum concentration of Ticagrelor. Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

Hydrocodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Hydrocodone. Monitor therapy

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Limit the maximum adult dose of lomitapide to 30 mg daily when used in combination with any weak CYP3A4 inhibitor. Consider therapy modification

Lovastatin: Ticagrelor may increase the serum concentration of Lovastatin. Management: Avoid using doses of lovastatin greater than 40 mg/day with ticagrelor. This specific recommendation is found in the U.S. prescribing information but not in the Canadian product monograph. Consider therapy modification

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Rivaroxaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simvastatin: Ticagrelor may increase the serum concentration of Simvastatin. Management: Avoid using doses of simvastatin greater than 40 mg/day with ticagrelor. This specific recommendation is found in the U.S. prescribing information but not in the Canadian product monograph. Consider therapy modification

St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vitamin E: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin E (Oral): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Adverse Reactions

As with all drugs which may affect hemostasis, bleeding is associated with ticagrelor. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the concurrent use of multiple agents which alter hemostasis and patient susceptibility.

>10%:

Endocrine & metabolic: Increased uric acid (22%)

Hematologic & oncologic: Major bleeding (4% to 12%)

Respiratory: Dyspnea (12% to ≤14%), dyspnea on exertion (2% to ≤14%)

1% to 10%:

Cardiovascular: Ventricular pause (2% to 6%), atrial fibrillation (4%), hypertension (4%), bradycardia (3%), chest pain (3%), hypotension (3%), cardiac failure (2%), peripheral edema (2%), ventricular tachycardia (2%), presyncope (≤2%), syncope (≤2%), angina pectoris (1%), palpitations (1%), sinus bradycardia (1%), ventricular premature contractions (1%)

Central nervous system: Headache (7%), dizziness (5%), noncardiac chest pain (4%), fatigue (3%), anxiety (2%), insomnia (2%), vertigo (2%), loss of consciousness (≤2%), depression (1%)

Dermatologic: Ecchymoses (2%), skin rash (2%), pruritus (1%), dermal hemorrhage

Endocrine & metabolic: Hypokalemia (2%), diabetes mellitus (1%), dyslipidemia (1%), hypercholesterolemia (1%)

Gastrointestinal: Diarrhea (4%), nausea (4%), vomiting (3%), abdominal pain (2%), constipation (2%), dyspepsia (2%), gastrointestinal hemorrhage (2%)

Genitourinary: Hematuria (2%), urinary tract infection (2%), urinary tract hemorrhage

Hematologic & oncologic: Minor bleeding (4% to 5%), bruise (4%), anemia (2%), hematoma (2%), hematoma (2%; puncture site), postprocedural hemorrhage (2%), subcutaneous hemorrhage

Neuromuscular & skeletal: Back pain (4%), arthralgia (2%), limb pain (2%), musculoskeletal chest pain (2%), musculoskeletal pain (2%), weakness (2%), myalgia (1%)

Renal: Increased serum creatinine (7% to 8%; transient; mechanism undetermined), renal failure (1%)

Respiratory: Epistaxis (1% to 6%), cough (5%), nasopharyngitis (2%), bronchitis (1%), pneumonia (1%)

Miscellaneous: Fever (3%)

<1% (Limited to important or life-threatening): Confusion, conjunctival hemorrhage, gastritis, gout, gynecomastia, hemarthrosis, hemopericardium, hemophthalmos, hemoptysis, hypersensitivity, intracranial hemorrhage (including fatalities), paresthesia, retinal hemorrhage, retroperitoneal hemorrhage, ventricular fibrillation

ALERT: U.S. Boxed Warning

Bleeding risk:

Ticagrelor, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding.

Do not use ticagrelor in patients with active pathological bleeding or a history of intracranial hemorrhage.

Do not start ticagrelor in patients undergoing urgent coronary artery bypass graft (CABG) surgery.

If possible, manage bleeding without discontinuing ticagrelor. Stopping ticagrelor increases the risk of subsequent cardiovascular events.

Aspirin dose and ticagrelor effectiveness:

Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor and should be avoided.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: [US Boxed Warning]: Ticagrelor increases the risk of bleeding including significant and sometimes fatal bleeding. Use is contraindicated in patients with active pathological bleeding (eg, peptic ulcer bleeding or intracranial hemorrhage) or history of intracranial hemorrhage. Additional risk factors for bleeding include propensity to bleed (eg, recent trauma or surgery, recent or recurrent GI bleeding, active PUD, moderate-severe hepatic impairment), CABG or other surgical procedure, concomitant use of medications that increase risk of bleeding (eg, warfarin, NSAIDs), and advanced age. Bleeding should be suspected if patient becomes hypotensive after undergoing recent coronary angiography, PCI, CABG, or other surgical procedure even if overt signs of bleeding do not exist. Where possible, manage bleeding without discontinuing ticagrelor as the risk of cardiovascular events is increased upon discontinuation. If discontinuation of ticagrelor is necessary, resume as soon as possible after the bleeding source is identified and controlled. Hemostatic benefits of platelet transfusions are not known; may inhibit transfused platelets.

• Hyperuricemia: Use with caution in patients with a history of hyperuricemia or gouty arthritis. Renal uptake and transport of uric acid are inhibited by ticagrelor and its active metabolite and the risk of hyperuricemia may be increased (Butler, 2012; Zhang, 2015). However, reports of gout did not differ between treatment groups in Platelet Inhibition and Patient Outcomes (PLATO) trial. Canadian labeling does not recommend use in patients with uric acid nephropathy.

• Respiratory: Dyspnea (often mild to moderate and transient) was observed more frequently in patients receiving ticagrelor compared to clopidogrel or aspirin alone during clinical trials (14% to 19% vs 6% to 8%) (Bonaca, 2015; Wallentin, 2009). Resolution of dyspnea was observed within 1 week in most patients (Wallentin, 2009). Patients with new, prolonged, or worsening dyspnea should be evaluated to rule out underlying disease. Ticagrelor-related dyspnea does not require specific treatment nor does it warrant therapy interruption; however, therapy should be discontinued in patients unable to tolerate ticagrelor-related dyspnea.

Disease-related concerns:

• Bleeding disorders: Use with caution in patients with platelet disorders, bleeding disorders, and/or at increased risk for bleeding (eg, PUD, trauma, or surgery).

• Cardiovascular disease: Use with caution in patients who are at an increased risk of bradycardia (eg, second- or third-degree AV block, sick sinus syndrome) or taking other bradycardic-inducing agents (eg, beta blockers, nondihydropyridine calcium channel blockers). Ventricular pauses ≥3 seconds were noted more frequently with ticagrelor than with clopidogrel during the first week after hospitalization for ACS in a substudy of the PLATO trial; however, most ventricular pauses were asymptomatic and transient (Scirica, 2011).

• Hepatic impairment: Use with caution in patients with moderate hepatic impairment due to limited experience. Use in severe hepatic impairment has not been studied; avoid use in these patients. Canadian labeling contraindicates use in moderate to severe impairment.

• Renal impairment: Creatinine levels may rise during therapy (mechanism undetermined); monitor renal function.

Concurrent drug therapy issues:

• Aspirin/other NSAIDs: [US Boxed Warning]: Maintenance doses of aspirin greater than 100 mg/day reduce the efficacy of ticagrelor and should be avoided. Use of higher maintenance doses of aspirin (ie, >100 mg/day) was associated with relatively unfavorable outcomes for ticagrelor versus clopidogrel in the PLATO trial (Gaglia, 2011; Wallentin, 2009). Canadian labeling recommends a maximum aspirin maintenance dose of 150 mg/day.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Surgical patients: [US Boxed Warning]: Avoid initiation of ticagrelor when urgent CABG surgery is planned; when possible, discontinue use at least 5 days before any surgery. Discontinue therapy 5 days before elective surgery (except in patients with cardiac stents who have not completed their full course of dual antiplatelet therapy; patient-specific situations need to be discussed with cardiologist) (ACCF/AHA [Hillis, 2011]). The ACCF/AHA STEMI guidelines recommend discontinuation for at least 24 hours prior to on-pump CABG if possible; off-pump CABG may be performed within 24 hours of ticagrelor administration if the benefits of prompt revascularization outweigh the risks of bleeding (ACCF/AHA [O’Gara, 2013]).

• Discontinuation of therapy: Premature discontinuation of therapy will increase the risk of MI, stroke, and death. If ticagrelor must be discontinued (eg, treatment of bleeding or for significant surgery), restart ticagrelor as soon as possible. Duration of therapy, in general, is determined by the type of stent placed (bare metal or drug eluting) and whether an ACS event was ongoing at the time of placement.

Monitoring Parameters

Signs of bleeding; hemoglobin and hematocrit periodically; renal function; uric acid levels (patients with gout or at risk of hyperuricemia); signs/symptoms of dyspnea; may consider platelet function testing to determine platelet inhibitory response if results of testing may alter management (ACCF/AHA [Anderson, 2013]).

Pregnancy Risk Factor

C

Pregnancy Considerations

Fetal mortality and/or abnormalities were observed in animal studies at doses greater than maximum recommended human doses. There are no adequate and well-controlled studies in pregnant women. Use only if potential benefits outweigh potential risk to fetus. The Canadian labeling recommends women of childbearing potential use appropriate contraceptive measures.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of hemorrhaging or dyspnea (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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