Ticagrelor

Ticagrelor is an antiplatelet agent belonging to the P2Y12 platelet inhibitor.

Ticagrelor is a P2Y12 platelet inhibitor used in patients with a history of myocardial infarction or with the acute coronary syndrome (ACS) to prevent future myocardial infarction, stroke, and cardiovascular death.

Absorption of ticagrelor occurs with a median Tmax of 1.5 h (range 1.0– 4.0). The mean absolute bioavailability of ticagrelor is about 36% (range 30%-42). The steady-state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%). 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 primary route of ticagrelor elimination is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). 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.

Ticagrelor shows common side effects like Dizziness and nausea.

Ticagrelor is available in the form Oral Tablet.

Ticagrelor is available in India, the US, the UK, Singapore, Switzerland, China, Australia, and Japan.

Ticagrelor belonging to the P2Y12 platelet inhibitor acts as an antiplatelet agent.

Ticagrelor 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.

The Onset of action of Ticagrelor is about 30 minutes.

The Duration of Action for Ticagrelor in the body is approximately 2-8 hours or 24 hours.

Ticagrelor is available in the form of an Oral Tablet.

Ticagrelor tablet is taken orally usually twice daily.

Ticagrelor is used along with Aspirin to reduce the risk of heart attack or stroke (damage to your brain resulting from reduced/blocked blood supply) or if you have a history of the acute coronary syndrome (conditions resulting from reduced blood flow to your heart). It works by preventing the formation of blood clots.

Ticagrelor is an antiplatelet agent belonging to the P2Y12 platelet inhibitor.

Ticagrelor is a P2Y₁₂ receptor antagonist. The P2Y₁₂ receptor couples with Gα_i2 and other G_i proteins which inhibit adenylyl cyclase. Gi-mediated signaling also activates PI3K, Akt, Rap1b, and potassium channels. The downstream effects of these activities mediate hemostasis and lead to platelet aggregation. Antagonism of the P2Y₁₂ receptor reduces the development of occlusive thromboses, which can reduce the risk of myocardial infarction and ischemic stroke.

Ticagrelor is approved for use in the following clinical indications

• Acute Coronary Syndrome or A History of Myocardial Infarction

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

• Coronary Artery Disease but No Prior Stroke or Myocardial Infarction

Ticagrelor 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 mellitus (T2DM).

• Acute Ischemic Stroke or Transient Ischemic Attack (TIA)

Ticagrelor 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).

Although not approved, there have been certain off-label indications. These include

• Percutaneous coronary intervention for stable ischemic heart disease.

• Acute Coronary Syndrome or A History of Myocardial Infarction

ST-elevation myocardial infarction:

• Percutaneous coronary intervention, primary:

Loading dose: Oral: 180 mg once as early as possible after diagnosis in combination with aspirin and a parenteral anticoagulant; followed by a maintenance dose.

Maintenance dose: Oral:

First 12 months after diagnosis: 90 mg twice daily beginning ~12 hours after the initial loading dose in combination with aspirin.

After 12 months from diagnosis: Reduce maintenance dose to 60 mg twice daily in combination with aspirin; in selected patients with ongoing high ischemic risk, may continue 90 mg twice daily in combination with aspirin.

• Post-fibrinolysis:

Loading dose: Oral: 180 mg once ≥12 hours after administration of fibrinolytic therapy (regardless of whether clopidogrel was co-administered at the time of diagnosis); followed by a maintenance dose.

Maintenance dose: Oral:

First 12 months after diagnosis: 90 mg twice daily beginning ~12 hours after the initial loading dose in combination with aspirin.

After 12 months from diagnosis: Reduce maintenance dose to 60 mg twice daily in combination with aspirin; in selected patients with ongoing high ischemic risk, may continue 90 mg twice daily in combination with aspirin.

• No reperfusion:

Loading dose: Oral: 180 mg once as early as possible after diagnosis in combination with aspirin and a parenteral anticoagulant; followed by a maintenance dose.

Maintenance dose: Oral:

First 12 months after diagnosis: 90 mg twice daily beginning ~12 hours after the initial loading dose in combination with aspirin.

After 12 months from diagnosis: Reduce maintenance dose to 60 mg twice daily in combination with aspirin; in selected patients with ongoing high ischemic risk, may continue 90 mg twice daily in combination with aspirin.

• Loading dose: Oral: 180 mg once as early as possible after diagnosis in combination with aspirin and a parenteral anticoagulant; followed by a maintenance dose. If coronary angiography is planned soon after diagnosis, it is reasonable to delay the initial loading dose until after coronary anatomy is known.

• Maintenance dose: Oral:

First 12 months after diagnosis: 90 mg twice daily beginning ~12 hours after the initial loading dose in combination with aspirin.

After 12 months from diagnosis: Reduce maintenance dose to 60 mg twice daily in combination with aspirin. Selected patients with ongoing high ischemic risk, may continue 90 mg twice daily in combination with aspirin.

• Coronary Artery Disease but No Prior Stroke or Myocardial Infarction

Oral: 60 mg twice daily in combination with aspirin; continue ticagrelor and aspirin indefinitely.

• Acute Ischemic Stroke or Transient Ischemic Attack (TIA)

Oral: Initial: 180 mg once in combination with aspirin, followed by 90 mg twice daily in combination with aspirin for 30 days.

• Percutaneous coronary intervention for stable ischemic heart disease (off-label use):

Loading dose: Oral: 180 mg once prior to percutaneous coronary intervention in combination with aspirin and a parenteral anticoagulant; followed by a maintenance dose.

Maintenance dose: Oral: 90 mg twice daily beginning ~12 hours after the initial loading dose in combination with aspirin.

Ticagrelor is available in the form of Oral Tablet.

• Dosage Adjustment in Hepatic impairment Patient

Mild impairment: No dosage adjustment necessary.

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

Severe impairment: Avoid use.

• Avoid grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of ticagrelor, which may increase its serum concentration.
• Avoid herbs and supplements with anticoagulant/antiplatelet activity. Herbs with antiplatelet activity may increase the risk of bleeding. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo Biloba.
• Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of ticagrelor and may reduce its serum concentration.

Ticagrelor is contraindicated in patients with

• History Of Intracranial Hemorrhage

Ticagrelor is contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population.

• Active Bleeding

Ticagrelor is contraindicated in patients with active pathological bleeding such as a peptic ulcer or intracranial hemorrhage.

• Hypersensitivity

Ticagrelor is contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product.

• Risk Of Bleeding

Drugs that inhibit platelet function including Ticagrelor increase the risk of bleeding.

• Patients Treated for Acute Ischemic Stroke or TIA

Patients at NIHSS >5 and patients receiving thrombolysis were excluded from THALES and the use of Ticagrelor in such patients is not recommended.

• Concomitant Aspirin Maintenance Dose for Patients Being Treated For ACS

In the management of patients with ACS, the use of Ticagrelor with maintenance doses of aspirin above 100 mg decreased the effectiveness of Ticagrelor. In such patients, use a maintenance dose of aspirin of 75-100 mg.

• Dyspnea

In clinical trials, about 14% (PLATO and PEGASUS) to 21% (THEMIS) of patients treated with Ticagrelor developed dyspnea. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment but led to study drug discontinuation in 0.9% (PLATO), 1.0% (THALES), 4.3% (PEGASUS), and 6.9% (THEMIS) of patients. In a sub-study of PLATO, 199 subjects underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment. If a patient develops new, prolonged, or worsened dyspnea that is determined to be related to Ticagrelor, no specific treatment is required; continue Ticagrelor without interruption if possible. In the case of intolerable dyspnea requiring discontinuation of Ticagrelor, consider prescribing another antiplatelet agent.

• Discontinuation Of Ticagrelor in Patients Treated for Coronary Artery Disease

Discontinuation of Ticagrelor will increase the risk of myocardial infarction, stroke, and death in patients being treated for coronary artery disease. If Ticagrelor must be temporarily discontinued (e.g., to treat bleeding or for significant surgery), restart it as soon as possible. When possible, interrupt therapy with Ticagrelor for five days prior to surgery which has a major risk of bleeding. Resume Ticagrelor as soon as hemostasis is achieved.

• Bradyarrhythmias

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 clinical studies and may be at increased risk of developing bradyarrhythmia with ticagrelor.

• Severe Hepatic Impairment

Avoid the use of Ticagrelor in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase the serum concentration of ticagrelor. There are no studies of Ticagrelor patients with severe hepatic impairment.

• Central Sleep Apnea

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 the following rechallenge. If central sleep apnea is suspected, consider a further clinical assessment.

It is not known whether ticagrelor or its active metabolites are excreted in human milk. Ticagrelor is excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Ticagrelor, a decision should be made whether to discontinue nursing or to discontinue Ticagrelor.

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant the use of the drug in pregnant women despite potential risks.

• Avoid grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of ticagrelor, which may increase its serum concentration.
• Avoid herbs and supplements with anticoagulant/antiplatelet activity. Herbs with antiplatelet activity may increase the risk of bleeding. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo Biloba.
• Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of ticagrelor and may reduce its serum concentration.

• Common Adverse effects

Dyspnea, ECG abnormality, Nausea, Hemorrhage, Dizziness, Gout, Increased serum creatinine, Increased uric acid.

• Rare Adverse effects

Atrioventricular block, bradycardia, Skin rash, Thrombotic thrombocytopenic purpura, Angioedema, Cheyne-Stokes respiration, sleep apnea.

• Strong CYP3A Inhibitors

Strong CYP3A inhibitors substantially increase ticagrelor exposure and so increase the risk of dyspnea, bleeding, and other adverse events. Avoid the use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin).

• Strong CYP3A Inducers

Strong CYP3A inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor. Avoid use with strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine, and phenobarbital).

• Aspirin

The use of Ticagrelor with aspirin maintenance doses above 100 mg reduced the effectiveness of Ticagrelor.

• Opioids

As with other oral P2Y₁₂ inhibitors, co-administration of opioid agonists delays and reduce the absorption of ticagrelor and its active metabolite presumably because of slowed gastric emptying. Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

• Simvastatin, Lovastatin

Ticagrelor increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin dose greater than 40 mg.

• Digoxin

Ticagrelor inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in Ticagrelor therapy.

The common side effects of Ticagrelor include the following

• Common

Dizziness, nausea.

• Rare

Shortness of breath that occurs while you are at rest, after a small amount of exercise, or after any physical activity, chest pain, fast, slow, pounding, or irregular heartbeat, rash, or swelling of the face, throat, tongue, lips, and eyes.

• Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Ticagrelor use in pregnant women. In animal studies, ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. Ticagrelor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. 20 mg/kg/day is approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on an mg/m2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on an mg/m2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. At the mid-dose of 100 mg/kg/day, delayed development of the liver and skeleton was seen. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on an mg/m2 basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis and sternebrae occurred. In a prenatal/postnatal study, pregnant rats received ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on an mg/m2 basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on an mg/m2 basis).

• Nursing Mothers

It is not known whether ticagrelor or its active metabolites are excreted in human milk. Ticagrelor is excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Ticagrelor, a decision should be made whether to discontinue nursing or to discontinue Ticagrelor.

• Pediatric Use

As per FDA, the safety and effectiveness of Ticagrelor in pediatric patients have not been established.

• Geriatric Use

In PLATO and PEGASUS, about half of the patients in each study were ≥65 years of age and about 15% were ≥75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients.

• There is currently no known treatment to reverse the effects of Ticagrelor, and ticagrelor is not expected to be dialyzable. Treatment of overdose should follow the local standard medical practice. Bleeding is the expected pharmacologic effect of overdosing. If bleeding occurs, appropriate supportive measures should be taken.
• Platelet transfusion did not reverse the antiplatelet effect of Ticagrelor in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding.
• Other effects of an overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG.

Pharmacodynamic

Ticagrelor is a P2Y₁₂ receptor antagonist that inhibits the formation of thromboses to reduce the risk of myocardial infarction and ischemic stroke. It has a moderate duration of action as it is given twice daily, and a wide therapeutic index as high single doses are well tolerated. Patients should be counseled regarding the risk of bleeding, dyspnea, and bradyarrhythmia.

Pharmacokinetics

• Absorption

Ticagrelor can be taken with or without food. Absorption of ticagrelor occurs with a median Tmax of 1.5 h (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 h (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. Ticagrelor 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. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. 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.

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