Agraplat

Each film-coated tablet contains: Ticagrelor 90mg.

Pharmacology: Pharmacodynamics: Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.
Pharmacokinetics: Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers.
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 t½ is approximately 7 hours for Ticagrelor and 9 hours for the active metabolite.
Toxicology: Preclinical Safety Data: Preclinical data for Ticagrelor and its major metabolite have not demonstrated unacceptable risk for adverse effects for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxic potential.
Gastrointestinal irritation was observed in several animal species at clinical relevant exposure levels.
In female rats, Ticagrelor at high dose showed an increased incidence of uterine tumours (adenocarcinomas) and an increased incidence of hepatic adenomas. The mechanism for uterine tumours is likely hormonal imbalance which can lead to tumours in rats. The mechanism for the hepatic adenomas is likely due to a rodent-specific enzyme induction in the liver. Thus, the carcinogenicity findings are considered unlikely to be relevant for humans.
In rats minor developmental anomalies were seen at a maternal toxic dose (safety margin of 5.1). In rabbits a slight delay in hepatic maturity and skeletal development was seen in fetuses from dams at high dose without showing maternal toxicity (safety margin of 4.5).
Studies in rats and rabbits have shown reproductive toxicity, with slightly reduced maternal body weight gain and reduced neonatal viability and birth weight, with delayed growth. Ticagrelor produced irregular cycles (mostly extended cycles) in female rats, but did not affect overall fertility in male and female rats. Pharmacokinetic studies performed with radio-labelled Ticagrelor have shown that the parent compound and its metabolites are excreted in the milk of rats.

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

Adult Dose: In the management of acute coronary syndrome (ACS), initiate Ticagrelor treatment with a 180 mg loading dose. Administer 90 mg twice daily during the first year after an ACS event.
Do not administer Ticagrelor with another oral P2Y12 platelet inhibitor.
Use Ticagrelor with a daily maintenance dose of aspirin of 75-100 mg.
A patient who misses a dose of Ticagrelor should take one tablet (their next dose) at its scheduled time.
Administration: For patients who are unable to swallow tablets whole, Ticagrelor tablets can be crushed, mixed with water and drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater). Or as prescribed by the physician.

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 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 overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG.

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 peptic ulcer or intracranial hemorrhage.
Hypersensitivity: Ticagrelor is contraindicated in patients with hypersensitivity (e.g., angioedema) to Ticagrelor or any component of the product.

General Risk of Bleeding: Drugs that inhibit platelet function including Ticagrelor increase the risk of bleeding. If possible, manage bleeding without discontinuing Ticagrelor. Stopping Ticagrelor increases the risk of subsequent cardiovascular events.
Concomitant Aspirin Maintenance Dose: In PLATO the use of Ticagrelor with maintenance doses of aspirin above 100 mg decreased the effectiveness of Ticagrelor. Therefore, after the initial loading dose of aspirin, use Ticagrelor with a maintenance dose of aspirin of 75-100 mg.
Dyspnea: 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: Discontinuation of Ticagrelor will increase the risk of myocardial infarction, stroke, and death. 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 that has a major risk of bleeding. Resume Ticagrelor as soon as hemostasis is achieved.
Severe Hepatic Impairment: Avoid use of Ticagrelor in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of Ticagrelor. There are no studies of Ticagrelor patients with severe hepatic impairment.
Hepatic Impairment: Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Avoid use of Ticagrelor in patients with severe hepatic impairment. There is limited experience with Ticagrelor in patients with moderate hepatic impairment; consider the risks and benefits of treatment, noting the probable increase in exposure to Ticagrelor. No dosage adjustment is needed in patients with mild hepatic impairment.
Renal Impairment: No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied.
Effects On Ability to Drive and Use Machine: There are no data on the effects of Ticagrelor on the ability to drive or use machines.
Use in Children: The safety and effectiveness of Ticagrelor in pediatric patients have not been established.

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.
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.

Most common adverse reactions are bleeding 12% and dyspnea 14%.
Post-Marketing Experience: The following adverse reactions have been identified during post-approval use of Ticagrelor. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency.
Immune system disorders: Hypersensitivity reactions including angioedema.
Skin and subcutaneous tissue disorders: Rash.

Strong CYP3A Inhibitors: Strong CYP3A inhibitors substantially increase Ticagrelor exposure and so increase the risk of dyspnea, bleeding, and other adverse events. Avoid 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: Use of Ticagrelor with aspirin maintenance doses above 100 mg reduced the effectiveness of Ticagrelor.
Simvastatin, Lovastatin: Ticagrelor increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg.
Digoxin: Ticagrelor inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in Ticagrelor therapy.

Store at temperatures not exceeding 30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AC24 - ticagrelor ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.

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