Tikleen

Uses

Tikleen is used for the prevention of atherothrombotic events in adult patients with Acute Coronary Syndromes (unstable angina, non ST elevation Myocardial Infarction [NSTEMI] or ST elevation Myocardial Infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG).

Tikleen is also used to associated treatment for these conditions: Cardiovascular Mortality, Myocardial Infarction, Myocardial Infarction First, Stent Thrombosis, Stroke

How Tikleen works

Tikleen is a P2Y₁₂ receptor antagonist.

The P2Y₁₂ receptor couples with Gα_i2 and other G_i proteins which inhibit adenylyl cyclase. G_i mediated signalling 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 development of occlusive thromboses, which can reduce the risk of myocardial infarction and ischemic stroke.

Dosage

Tikleen dosage

Tikleen treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily. Patients taking Tikleen should also take aspirin daily, unless specifically contraindicated. Following an initial dose of aspirin (usually 325 mg), Tikleen should be used with a maintenance dose of aspirin of 75-100 mg. Maintenance dose of Aspirin above 100 mg decreased the efficacy of Tikleen. So, maintenance dose of aspirin above 100 mg should be avoided.

A patient who misses a dose of Tikleen should take only one 90 mg tablet (the next dose) at its scheduled time. Patients treated with Clopidogrel can be directly switched to Tikleen if needed. Switching from prasugrel to ticagrelor has not been investigated.

Treatment is recommended for up to 12 months unless discontinuation of Tikleen is clinically indicated. Tikleen can be administered with or without food.

Side Effects

Dyspnea,bleeding,headache,cough,dizziness,nausea,atrial fibrillation, hypertension, non-cardiac chest pain, diarrhea, back pain, hypotension, fatigue, chest pain.

Toxicity

Patients experiencing an overdose may present with bleeding, nausea, vomiting, diarrhea, and ventricular pauses. Overdose can be managed through symptomatic and supportive treatment, including ECG monitoring. Dialysis is not expected to remove ticagrelor from the blood due to it being highly protein bound.

Precaution

General Risk of Bleeding: Drugs that inhibit platelet function including Tikleen increase the risk of bleeding.

Concomitant Aspirin Maintenance Dose: Use of Tikleen with maintenance doses of aspirin above 100 mg decreased the effectiveness of Tikleen. Therefore, after the initial loading dose of aspirin (usually 325 mg), use Tikleen with a maintenance dose of aspirin of 75-100 mg.

Moderate Hepatic Impairment: Tikleen has not been studied in patients with moderate hepatic impairment.

Discontinuation of Tikleen: Discontinuation of Tikleen will increase the risk of myocardial infarction, stent thrombosis, and death.

Interaction

CYP3A inhibitors: Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin).

CYP3A inducers: Avoid use with potent inducers of CYP3A (e.g., rifampin, dexamethasone, phenytoin,carbamazepine and phenobarbital).

Aspirin: Use of Tikleen with aspirin maintenance doses above 100 mg reduced the effectiveness ofTikleen.

Simvastatin, Lovastatin: Tikleen will result in higher serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg.

Digoxin: Because of inhibition of the P-glycoprotein transporter, monitor digoxin levels with initiation of or any change in ticagrelor therapy.

Other Concomitant Therapy: Tikleen can be administered with unfractionated or low-molecular-weight heparin, GPIIb/llla inhibitors, proton pump inhibitors, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers.

Food Interaction

• 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.
• Take with or without food.

Tikleen Drug Interaction

Major: apixabanModerate: aspirin, aspirin, aspirin, omega-3 polyunsaturated fatty acids, clopidogrelMinor: atorvastatin, metoprolol, metoprololUnknown: ubiquinone, rosuvastatin, empagliflozin, insulin glargine, furosemide, nitroglycerin, acetaminophen, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Tikleen Disease Interaction

Major: bleeding, liver dysfunctionModerate: bradyarrhythmias, dyspnea, renal impairment

Volume of Distribution

The steady state volume of distribution of ticagrelor is 88 L.

Elimination Route

Tikleen is 36% orally bioavailable. A single 200mg oral dose of ticagrelor reaches a C_max of 923ng/mL, with a T_max of 1.5 hours and an AUC of 6675ng*h/mL. The active metabolite of ticagrelor reaches a C_max of 264ng/mL, with a T_max of 3.0 hours and an AUC of 2538ng*h/mL.

Half Life

Tikleen has a plasma half life of approximately 8 hours, while the active metabolite has a plasma half life of approximately 12 hours.

Clearance

The renal clearance of ticagrelor is 0.00584L/h.

Elimination Route

A radiolabelled dose of ticagrelor is 57.8% recovered in feces and 26.5% recovered in urine. Less than 1% of the dose is recovered as the unmetabolized parent drug. The active metabolite AC-C124910XX makes up 21.7% of the recovery in the feces. The metabolite AR-C133913XX makes up 9.2% of the recovery in the urine and 2.7% of the recovery in the feces. Other minor metabolites are predominantly recovered in the urine.

Pregnancy & Breastfeeding use

Pregnancy category C. There are no or limited amount of data from the use of Tikleen in pregnant women.Tikleen is not recommended during pregnancy.

Nursing mothers: Available pharmacodynamic/toxicological data in animals have shown excretion of Tikleen and its active metabolites in milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from ticagrelor therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the women.

Contraindication

Tikleen is contraindicated in case of-

• Hypersensitivity to Tikleen or to any of the excipients
• Active pathological bleeding (peptic ulcer)
• History of intracranial haemorrhage
• Moderate to severe hepatic impairment
• Co-administration of Tikleen with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir)

Special Warning

Pediatric Use: The safety and effectiveness of Tikleen in pediatric patients have not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed in geriatric patients.

Hepatic Impairment: Tikleen has not been studied in the patients with moderate or severe hepatic impairment. Tikleen is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Hence,

Renal Impairment: No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied.

Acute Overdose

There is currently no known antidote to reverse the effects ofTikleen and it is not expected to be dialysable.Treatment of overdose should follow local standard medical practice.The expected effect of excessive ticagrelor dosing is prolonged duration of bleeding risk associated with platelet inhibition. If bleeding occurs appropriate supportive measures should be taken.

Storage Condition

Protect from light & moisture. Store below 25° C. Keep out of reach of children.

Innovators Monograph

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