Ticagrelor (Brilinta) - Uses, Dose, MOA, Brands, Side effects

Ticagrelor (Brilinta) is a platelet aggregation inhibitor. It inhibits the activation of platelets by binding to the ADP receptors making them less sticky. It has a rapid onset of action compared to clopidogrel and short half-life.

Ticagrelor Uses:

It is used to reduce the risks of cardiovascular deaths, myocardial infarction, and stroke in patients with a history of myocardial infarction or acute coronary syndrome. It is also used to reduce the risks of stent thrombosis in patients who have had angioplasty for coronary heart disease. In aspirin-intolerant patients, it may be used as a blood thinner for non-ST-elevation acute coronary syndrome.

Ticagrelor vs Clopidogrel:

Ticagrelor and Clopidogrel both inhibit platelet aggregation resulting in an enhanced blood flow especially in the narrow blood vessels (arterioles and small arteries). However, there are minor differences in their efficacies, onset, and duration of actions.

The following table is a comparison of the two drugs:

Ticagrelor (Brilinta)	Clopidogrel (Plavix)
It inhibits P2Y12 reversibly	It irreversibly inhibits platelet aggregation
It is associated with a greater platelet inhibition	It has a modest antiplatelet activity
It has a rapid onset of action	It has a slow onset of action
Direct antiplatelet activity	Functions indirectly after it is metabolized to the active compound
The response is consistent and hepatic function has little effect on its efficacy as it is not a prodrug and does not require metabolic activation	Variable response (partially depends on the liver function)
Bleeding is more common	Bleeding less common with clopidogrel
Dyspnea is more common	Dyspnea is not a side effect of this drug
Syncope is more common	Syncope less common
Greater than 3-seconds ventricular pauses were more common in the ticagrelor group	Ventricular pauses uncommon in this group
It increases the serum uric acid levels	It has little effect on uric acid levels
An increase in the serum creatinine has been noted in clinical trials	It has little effect on serum creatinine values.
Less number of patients developed neoplasms during clinical trials in the ticagrelor group.	Neoplasms arising during treatment

Ticagrelor has also been found to be superior to aspirin in patients with stroke and other vascular disorders at the expense of excessive bleeding. It has similar efficacy and rapid onset of action as prasugrel, however, unexplained dyspnea is more common with prasugrel.

Ticagrelor (Brilinta) Dose in Adults

Ticagrelor (Brilinta) dosage in the treatment of acute coronary syndrome (ACS):

Non-ST-elevation acute coronary syndromes and ST-segment elevation myocardial infarction (STEMI):
- A loading dose of 180 mg is given orally or via a nasogastric tube with 325 mg of aspirin.
- The loading dose is followed by the maintenance dose of 90 mg twice daily.
- The maintenance dose should be initiated 12 hours after the loading dose with a low dose of aspirin.
- After 12 months of therapy, the dose of ticagrelor should be reduced to 60 mg twice daily.
- Aspirin should be continued indefinitely in patients with STEMI and NSTE-ACS (non-ST-elevation acute coronary syndrome)
Duration of ticagrelor (in combination with aspirin) after stent placement:
- Dual antiplatelet (a combination of aspirin and either clopidogrel or ticagrelor) should be given for a period of one year to avoid premature stent thrombosis that may be fatal.
- Patients with drug-eluting stents who are at a higher risk of bleeding may be given dual antiplatelet therapy for six months
Conversion from clopidogrel to ticagrelor:
- Ticagrelor therapy (loading dose or maintenance dose) may be initiated 24 hours after the last dose of clopidogrel.
- A loading dose of ticagrelor is preferred (regardless of clopidogrel use) in patients who are in the acute phase of an acute coronary syndrome.

Ticagrelor (Brilinta) Dose in Childrens

It is not recommended for use in children. The safety and efficacy has not been established in children.

Ticagrelor pregnancy risk Cateogory C

Its use in pregnancy is not known.
It is unknown if the drug will be excreted into breastmilk.
Avoid it during pregnancy and breastfeeding.

Ticagrelor dosage in kidney disease:

Adjustment in the dose is not necessary.
It is not dialyzable and dose adjustment in patients undergoing hemodialysis is not necessary.

Ticagrelor (Brilinta) dosage in liver disease:

Mild impairment:
- Dosage adjustment is not necessary.
Moderate impairment:
- It should be used with caution in patients with moderate hepatic dysfunction as it is metabolized by the liver.
Severe impairment:
- In severe hepatic impairment, its use should be avoided.

Side effects of Ticagrelor:

Since it inhibits platelet aggregation, bleeding is the most common side effect.
Elderly patients and those with concomitant risk factors should be observed for bleeding diathesis including measuring hemoglobin and hematocrit values.

Ticagrelor side effects (common):

Respiratory:
- Dyspnea

Cardiovascular:
- ECG Abnormality
- Presyncope
- Syncope
Central Nervous System:
- Dizziness
- Loss Of Consciousness
Gastrointestinal:
- Nausea
Hematologic & Oncologic:
- Major Hemorrhage
- Minor Hemorrhage
Renal:
- Increased Serum Creatinine

Endocrine & metabolic:
- Increased uric acid

Ticagrelor Contraindications:

Allergy to ticagrelor, or any component of this formulation
Patients with active major bleeding (e.g. Patients with active major bleeding (e.g., peptic ulcer or intracranial bleeding).
Patients who have had intracranial bleeding in the past.
Hepatic dysfunction ranging from mild to severe
Concomitant administration CYP3A4 inhibitors such as clarithromycin and ketoconazole like clarithromycin, ritonavir or atazanavir and nefazodone.

Warnings and precautions

Bleeding: [US Boxed Warning]
- Patients with active peptic bleeding or other major external or intravascular bleeding, such as intracranial hemorhage, are not advised to take Ticagrelor.
- This can cause life-threatening bleeding, especially for patients at high risk.
- Patients with a higher risk for bleeding include:
  - Recent trauma, CABG, surgery or other surgical procedures
  - Recent or recurrent gastrointestinal bleeding
  - Hepatic impairments ranging from moderate to severe
  - concomitant use of anticoagulants such as warfarin and nonsteroidal anti-inflammatory drugs
  - elderly patients
- It is important to identify and manage bleeding as soon as possible, even if you are unable to discontinue ticagrelor.
- The risk of developing cardiovascular problems increases upon discontinuation.
- Transfusion of platelets is not a useful tool because it can inhibit platelet aggregation.
Bradyarrhythmias:
- Patients with second- and third-degree heart block should not use it. There is a risk of Ventricular pauses or bradyarrhythmias.
- Additional cautions are:
  - Sick sinus syndrome,
  - Bradyarrhythmias can cause syncope
  - Patients who are taking beta-blockers and non-dihydropyridine calcium channels blockers like verapamil or diltiazem may also be using drugs such as verapamil.
Hyperuricemia:
- It can cause impairment in the renal uptake.
- Patients with gout and those at a higher risk of hyperuricemia should be advised the drug with caution.
- These patients should have their uric acid levels checked frequently.
Respiratory system
- Ticagrelor-related dyspnea was reported in patients who took clopidogrel or aspirin.
- It is important to stop all treatment.
- It doesn't require any particular type of therapy.
Thrombotic tubocytopenic purpura
- TTP (thrombotic-thrombocytopenic purpura), has been described in cases.
- To avoid death, it should be detected earlier and plasmapheresis should also be considered.
Bleeding disorders:
- Patients with bleeding disorders should use it with caution.
- Patients at high risk of bleeding, such as those who have had surgery, patients suffering from peptic ulcer disease or after trauma, should not take the drug.
Hepatic impairment
- In severe liver disease, it should be avoided.
- It should only be used in moderate hepatic dysfunction.
Renal impairment
- Patients at high risk of developing renal impairment should not use it. Monitor your serum creatinine levels regularly as they may increase.

Ticagrelor: Drug Interaction

Risk Factor C (Monitor therapy)
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.)	May enhance the antiplatelet effect of other Agents with Antiplatelet Properties.
Anticoagulants	Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Exceptions: Bemiparin; Enoxaparin; Heparin.
AtorvaSTATin	Ticagrelor may increase the serum concentration of AtorvaSTATin.
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Cephalothin	Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased.
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.
CycloSPORINE (Systemic)	May increase the serum concentration of Ticagrelor.
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate	May increase the serum concentration of Ticagrelor.
Dasatinib	May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
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.
Digoxin	Ticagrelor may increase the serum concentration of Digoxin.
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Fat Emulsion (Fish Oil Based)	May enhance the adverse/toxic effect of Agents with Antiplatelet Properties.
FentaNYL	May diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). FentaNYL may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors).
Glucosamine	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Grapefruit Juice	May increase the serum concentration of Ticagrelor.
Ibritumomab Tiuxetan	Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding.
Ibrutinib	May enhance the adverse/toxic effect of Agents with Antiplatelet Properties.
Inotersen	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Ivosidenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Limaprost	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Multivitamins/Fluoride (with ADE)	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Multivitamins/Minerals (with ADEK, Folate, Iron)	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Multivitamins/Minerals (with AE, No Iron)	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Obinutuzumab	Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased.
Omega-3 Fatty Acids	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
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.
Pentoxifylline	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Prostacyclin Analogues	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Salicylates	Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Thrombolytic Agents	Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
Tipranavir	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Vitamin E (Systemic)	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Risk Factor D (Consider therapy modification)
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.
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.
Bemiparin	Agents with Antiplatelet Properties may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin with antiplatelet agents. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding.
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.
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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).
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.
Enoxaparin	Agents with Antiplatelet Properties may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding.
Heparin	Agents with Antiplatelet Properties may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required.
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry)	May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Management: Avoid combination when possible. If used, monitor more closely for evidence of bleeding. Discontinue herbal products with anticoagulant or antiplatelet actions 2 weeks prior to surgical, dental, or invasive procedures.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
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.
Morphine (Systemic)	May diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). Morphine (Systemic) may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors). Management: Consider alternative anti-ischemic/analgesic therapies (eg, beta-blockers, nitroglycerin) in patients with acute coronary syndromes treated with a P2Y12 inhibitor when possible. The risks associated with other opioids are unknown.
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.
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.
St John's Wort	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.
Risk Factor X (Avoid combination)
CYP3A4 Inducers (Strong)	May decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ticagrelor.
CYP3A4 Inhibitors (Strong)	May decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor.
Urokinase	Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase.

What to monitor with Ticagrelor (Brilinta)?

Monitor the patient for signs of bleeding
Monitor hemoglobin and hematocrit
Renal function
Uric acid levels in patients with or at risk of hyperuricemia
Dyspnea

How to administer Ticagrelor (Brilinta)?

It may be administered with or without a meal.
Patients who can not swallow the whole tablet may be given the tablet crushed and mixed with water.
It can also be administered via a nasogastric tube.
If a dose is missed, a double dose is not recommended.
The drug should be taken at the next scheduled time.

Ticagrelor (Brilinta) mechanism of action:

Ticagrelor (Brilinta), reduces platelet aggregation, making them less sticky to vascular surfaces.
It does this by binding in a reverse fashion to the ADP P2Y receptor at the platelet surface.
This prevents ADP-mediated activation the GPIIb/IIIa complex.
Because binding is irreversible, platelet function activity is dependent on serum concentrations of drug and its metabolites.
After a loading dose 180 mg, platelet aggregation is reduced by 41% in half an hour.
This is similar to Clopidogrel 600m eight hours after drug administration.

Maximum effectThe peak effect is visible in just two hours and results in 88% platelet aggregation inhibition. If the tablet is crushed, peak effects may be visible as soon as one hour after being taken. The inhibition of platelet aggregation is maintained at 87-89% for 2-8 hours, and 58% for 24 hours. Inhibition of platelet activity after 56 hours and 110hrs is respectively 30% and 10%. It isRapidly absorbedIt is more than 97% protein-bound. It isMetabolizedBy the hepatic CYP3A4/5 conversion to an active metabolite AR-C124910XX TheBioavailabilityIt is approximately 36% (ranging between 30% and 42%) Half-life eliminationThe time between the parent drug and the active metabolite takes approximately 7 hours. It isexcretedIt is mainly through feces (58%) or urine (26%).