BRILINTA pharmacology is different than that of thienopyridines1

BRILINTA belongs to a different chemical class than other oral antiplatelets (OAPs) and has different pharmacological properties1

The first and only OAP in a chemical class called cyclo-pentyl-triazolo-pyrimidine (CPTP)1

The first and only OAP in a chemical class called cyclo-pentyl-triazolo-pyrimidine (CPTP)1

 

 

Reversibly interacts with the P2Y12 receptor

Active without metabolism

Metabolism independent of CYP2C19 genotype

Primary CYP enzyme for metabolism

CPTP

BRILINTA2

Reversibly interacts with the P2Y12 receptorYes

Active without metabolismYes

Metabolism independent of CYP2C19 genotypeYes

Primary CYP enzyme for metabolism3A4

THIENOPYRIDINES

THIENOPYRIDINES

CLOPIDOGREL3

Reversibly interacts with the P2Y12 receptorNo

Active without metabolismNo

Metabolism independent of CYP2C19 genotypeNo

Primary CYP enzyme for metabolism2C19

 

THIENOPYRIDINES

PRASUGREL4

Reversibly interacts with the P2Y12 receptorNo

Active without metabolismNo

Metabolism independent of CYP2C19 genotypeYes

Primary CYP enzyme for metabolism3A4 and 2B6

  • Ticagrelor and its active metabolite are approximately equipotent2
  • It is not known how pharmacology or chemical class correlates to clinical efficacy or safety results
  • There are no adequate, well-controlled, head-to-head clinical trials comparing BRILINTA and thienopyridines in patients with acute ischemic stroke or high-risk CAD without a history of MI or stroke

Pharmacokinetics2

Absorption

  • Absorption of ticagrelor occurs with a median tmax of 1.5 hours (range 1.0-4.0). The formation of the major circulating metabolite AR-C124910XX (active) from ticagrelor occurs with a median tmax of 2.5 hours (range 1.5-5.0)
  • The mean absolute bioavailability of ticagrelor is about 36% (range 30-42%). Ingestion of a high-fat meal had no effect on ticagrelor Cmax, but resulted in a 21% increase in AUC. The Cmax of its major metabolite was decreased by 22% with no change in AUC. BRILINTA can be taken with or without food
  • BRILINTA as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and Cmax within 80-125% for ticagrelor and AR-C124910XX) with a median tmax of 1.0 hour (range 1.0-4.0) for ticagrelor and 2.0 hours (range 1.0-8.0) for AR-C124910XX

Distribution

  • The steady-state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%)

Metabolism

  • CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-40% of the exposure of ticagrelor

Excretion

  • The primary route of ticagrelor elimination is hepatic metabolism
  • The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion
  • The mean t1/2 is approximately 7 hours for ticagrelor and 9 hours for the active metabolite

Pharmacodynamics

BRILINTA provided rapid onset and high inhibition of platelet aggregation (IPA) compared to clopidogrel5,6

Assessment of IPA over 8 hours after 180-mg loading dose2,6

Assessment of IPA over 8 Hours
Assessment of IPA over 8 Hours

In a multicenter, randomized, double-blind study, patients with stable coronary artery disease (CAD) who were taking aspirin therapy (75 mg to 100 mg per day) received BRILINTA (180-mg loading dose, 90-mg twice-daily maintenance dose), clopidogrel (600-mg loading dose, 75-mg once-daily maintenance dose), or placebo for 6 weeks.5

     

  • It is not known how bleeding or thrombotic risk tracks with IPA for either BRILINTA or clopidogrel2
  • The maximum IPA effect of BRILINTA was 88% at around 2 hours and was maintained for at least 8 hours2,5
  • IPA was higher in the BRILINTA group at all time points2
  • Patients can be transitioned from clopidogrel to BRILINTA without interruption of antiplatelet effect2
    • The transition from clopidogrel to BRILINTA resulted in an absolute IPA increase of 26.4%, and the transition from BRILINTA to clopidogrel resulted in an absolute IPA decrease of 24.5%2
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References
  1. Husted S, van Giezen JJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther. 2009;27(4):259-274.
  2. BRILINTA® (ticagrelor) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2024.
  3. Plavix® (clopidogrel bisulfate) [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2022.
  4. Effient® (prasugrel) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2019.
  5. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009;120(25):2577-2585.
  6. Data on File, REF-5072. AstraZeneca Pharmaceuticals LP.
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IMPORTANT SAFETY INFORMATION FOR BRILINTA® (ticagrelor) 60-MG AND 90-MG TABLETS

WARNING: BLEEDING RISK

  • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding
  • Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage
  • Do not start BRILINTA in patients undergoing urgent coronary artery bypass graft surgery
  • If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events

CONTRAINDICATIONS

  • BRILINTA is contraindicated in patients with a history of intracranial hemorrhage or active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is also contraindicated in patients with hypersensitivity (eg, angioedema) to ticagrelor or any component of the product

WARNINGS AND PRECAUTIONS

  • Dyspnea was reported more frequently with BRILINTA than in patients treated with control agents. Dyspnea from BRILINTA is often self-limiting
  • In patients being treated for coronary artery disease, discontinuation of BRILINTA will increase the risk of MI, stroke, and death. When possible, interrupt therapy with BRILINTA for 5 days prior to surgery that has a major risk of bleeding. If BRILINTA must be temporarily discontinued, restart as soon as possible
  • Ticagrelor can cause ventricular pauses. Bradyarrhythmias including AV block have been reported in the post-marketing setting. Clinical trials excluded patients at increased risk of bradyarrhythmias not protected by a pacemaker, and they may be at increased risk of developing bradyarrhythmias
  • Avoid use of BRILINTA in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor and there are no studies of BRILINTA in these patients
  • Central sleep apnea (CSA) including Cheyne-Stokes respiration (CSR) has been reported in the post-marketing setting in patients taking ticagrelor, including recurrence or worsening of CSA/CSR following rechallenge
  • In patients with Heparin Induced Thrombocytopenia (HIT): False-negative results for HIT-related platelet functional tests, including the heparin-induced platelet aggregation (HIPA) assay, have been reported with BRILINTA. BRILINTA is not expected to impact PF4 antibody testing for HIT

ADVERSE REACTIONS

  • The most common adverse reactions (>5%) associated with the use of BRILINTA included bleeding and dyspnea

DRUG INTERACTIONS

  • Avoid use with strong CYP3A inhibitors and strong CYP3A inducers. BRILINTA is metabolized by CYP3A4/5. Strong inhibitors substantially increase ticagrelor exposure and so increase the risk of adverse events. Strong inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor
  • As with other oral P2Y12 inhibitors, co-administration of opioid agonists delays and reduces the absorption of ticagrelor. Consider the use of a parenteral anti-platelet in ACS patients requiring co-administration
  • Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse events
  • Rosuvastatin plasma concentrations may increase because rosuvastatin is a breast cancer resistance protein (BCRP) substrate. Monitor for statin-related adverse effects
  • Monitor digoxin levels with initiation of, or change in, BRILINTA therapy

SPECIAL POPULATIONS

  • Lactation: Breastfeeding is not recommended

INDICATIONS

BRILINTA is indicated to reduce the risk of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction. For at least the first 12 months following ACS, it is superior to clopidogrel. BRILINTA also reduces the risk of stent thrombosis in patients who have been stented for the treatment of ACS.

BRILINTA is indicated to reduce the risk of a first MI or stroke in patients with coronary artery disease (CAD) at high risk for such events. While use is not limited to this setting, the efficacy of ticagrelor was established in a population with type 2 diabetes.

BRILINTA is indicated to reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale Score ≤5) or high-risk transient ischemic attack (TIA).

DOSING

In the management of ACS, initiate BRILINTA treatment with a 180-mg loading dose. Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily. Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg. However, in patients who have undergone PCI, consider single antiplatelet therapy with BRILINTA based on the evolving risk for thrombotic versus bleeding events.

In patients with CAD but no prior stroke or MI, administer 60 mg twice daily. Generally, use BRILINTA with a daily maintenance dose of aspirin of 75 mg to 100 mg.

In patients with acute ischemic stroke or high-risk TIA, initiate treatment with a 180-mg loading dose of BRILINTA and then continue with 90 mg twice daily for up to 30 days. Use BRILINTA with a loading dose of aspirin (300 mg to 325 mg) and a daily maintenance dose of aspirin of 75 mg to 100 mg.

Please read full Prescribing Information, including Boxed WARNING, and Medication Guide.

You may report side effects related to AstraZeneca products.

 

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