Briclot

Briclot

Manufacturer:

Dexa Medica
Full Prescribing Info
Contents
Ticagrelor.
Description
Each film coated tablet contains: Ticagrelor 90 mg.
Action
Pharmacology: 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: The AUC0-t for the test drug was 4356.26 ng.hour/ml. The AUC0-inf for the test drug was 4561.14 ng.hour/ml. The Cmax for the test drug was 726.95 ng/ml.
The geometric mean ratios (90% confidence intervals) of the test drug/comparator drug for ticagrelor were 107.12% (99.75-115.03%) for AUC0-t and 111.02% (101.48-121.46%) for Cmax. The 90% confidence intervals of the test/comparator ratios for both AUC0-t and Cmax of ticagrelor were within the acceptance range for bioequivalence.
The mean (SD) elimination half-life (t½) of ticagrelor for the test drug was 6.22 (0.84) hours. The half-life values of the test and the comparator drug were not significantly different.
The median (range) of the time to reach maximum ticagrelor plasma concentration (tmax) of the test drug was 1.50 (1.00-4.00) hours. The tmax values of the test drug and the comparator drug were not significantly different.
Special populations: The effects of age, gender, ethnicity, renal impairment, and mild hepatic impairment on the pharmacokinetics of ticagrelor are modest and do not require dose adjustment.
Pediatric: Ticagrelor has not been evaluated in a pediatric population (see Use in specific populations under Precautions).
Body weight: No dose adjustment is necessary for ticagrelor based on weight.
Smoking: Habitual smoking increased population mean clearance of ticagrelor by approximately 22% when compared to non-smokers. No dose adjustment is necessary for ticagrelor based on smoking status.
Effects of other drugs on ticagrelor: CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) substantially increase ticagrelor exposure. Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem). CYP3A inducers (e.g., rifampin) substantially reduce ticagrelor blood levels. P-gp inhibitors (e.g., ciclosporin) increase ticagrelor exposure.
Effects of ticagrelor on other drugs: Ticagrelor and its major active metabolite are weak inhibitors of CYP3A4, potential activators of CYP3A5 and inhibitors of the P-gp transporter. Ticagrelor and AR-C124910XX were shown to have no inhibitory effect on human CYP1A2, CYP2C19, and CYP2E1 activity.
Pharmacogenetics: The rate of thrombotic cardiovascular events in the ticagrelor arm did not depend on CYP2C19 loss of function status.
Indications/Uses
Ticagrelor coadministered with acetylsalicylic acid 75-100 mg is indicated for the prevention of thrombotic events (cardiovascular death, myocardial infarction, and stroke) in patients with acute coronary syndromes (ACS) [unstable angina, non-ST elevation myocardial infarction (NSTEMI) or ST elevation myocardial infarction (STEMI)] including patients managed with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).
Dosage/Direction for Use
Patients taking ticagrelor should also take a daily low maintenance dose of acetylsalicylic acid 75-100 mg, unless specifically contraindicated.
Acute coronary syndromes: Ticagrelor treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily.
Missed dose: Lapses in therapy should also be avoided. A patient who misses a dose of ticagrelor should take only one tablet (their next dose) as its scheduled time.
Special populations: Elderly: No dose adjustment is required in elderly.
Renal impairment: No dose adjustment is necessary for patients with renal impairment. No information is available concerning treatment of patients on renal dialysis and therefore ticagrelor is not recommended in these patients.
Hepatic impairment: Ticagrelor has not been studied in patients with severe hepatic impairment and its use in these patients is therefore contraindicated. Only limited information is available in patients with moderate hepatic impairment. Dose adjustment is not recommended, but ticagrelor should be used with caution. No dose adjustment is necessary for patients with mild hepatic impairment.
Pediatric population: The safety and efficacy of ticagrelor in children below the age of 18 years have not been established. No data are available.
Method of administration: For oral use.
Ticagrelor can be administered with or without food.
For patients who are unable to swallow the tablets whole, the tablets can be crushed to a fine powder and mixed in half a glass of water and drunk immediately. The glass should be rinsed with a further half glass of water and the contents drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater). It is important to flush the nasogastric tube through with water after administration of the mixture.
Overdosage
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 standar 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.
Contraindications
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 (see Precautions and Adverse Reactions).
Severe hepatic impairment: Ticagrelor is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure, and it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins.
Hypersensitivity: Ticagrelor is contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product (see Adverse Reactions).
Coadministration with strong CYP3A4 inhibitors: Coadministration of ticagrelor with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir) is contraindicated, as coadministration may lead to a substantial increase in exposure to ticagrelor.
Warnings
Bleeding Risk: Ticagrelor, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding.
Do not use ticagrelor in patients with active pathological bleeding or a history of intracranial hemorrhage.
Do not start ticagrelor in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue ticagrelor at least 5 days prior to any surgery.
Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of ticagrelor.
If possible, manage bleeding without discontinuing ticagrelor. Stopping ticagrelor increases the risk of subsequent cardiovascular events.
Acetylsalicylic acid (Aspirin) dose and Ticagrelor effectiveness: Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor and should be avoided. After any initial dose, use with aspirin 75-100 mg per day.
Special Precautions
General risk of bleeding: Drugs that inhibit platelet function including ticagrelor increase the risk of bleeding. Ticagrelor increased the overall risk of bleeding (major + minor) to a somewhat greater extent than did clopidogrel. The increase was seen for non-CABG-related bleeding, but not for CABG-related bleeding. Fatal and life-threatening bleeding rates were not increased (see Adverse Reactions).
In general, risk factors for bleeding include older age, a history of bleeding disorders, performance of percutaneous invasive procedures, and concomitant use of medications that increase the risk of bleeding (e.g., anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal anti-inflammatory drugs [NSAIDs]).
When possible, discontinue ticagrelor five days prior to surgery. Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures, even if the patient does not have any signs of bleeding.
If possible, manage bleeding without discontinuing ticagrelor. Stopping ticagrelor increases the risk of subsequent cardiovascular events (see Warnings and Adverse Reactions).
Concomitant aspirin maintenance dose: Use of ticagrelor with maintenance doses of aspirin above 100 mg decreased the effectiveness of ticagrelor. Therefore, after the initial loading dose of aspirin (usually 325 mg), use ticagrelor with a maintenance dose of aspirin of 75-100 mg (see Dosage & Administration).
Dyspnea: Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment. If a patient develops new, prolonged, or worsened dyspnea during treatment with ticagrelor, exclude underlying diseases that may require treatment. If dyspnea is determined to be related to ticagrelor, no specific treatment is required; continue ticagrelor without interruption. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment.
Discontinuation of ticagrelor: Avoid interruption of ticagrelor treatment. If ticagrelor must be temporarily discontinued (e.g., to treat bleeding or for elective surgery), restart it as soon as possible. Discontinuation of ticagrelor will increase the risk of myocardial infarction, stent thrombosis, and death.
Strong inhibitors of cytochrome CYP3A: Ticagrelor is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole (see Interactions).
Cytochrome CYP3A potent inducers: Avoid use with potent CYP3A inducers, such as rifampin, phenytoin, carbamazepine, and phenobarbital (see Interactions).
Surgery: Patients should be advised to inform physicians and dentists that they are taking ticagrelor before any surgery is scheduled and before any new medicinal product is taken. Patients undergoing coronary artery bypass grafting (CABG), ticagrelor had more bleeding than clopidogrel when stopped within 1 day prior to surgery but a similar rate of major bleeds compared to clopidogrel after stopping therapy 2 or more days before surgery. If a patient is to undergo elective surgery and antiplatelet effect is not desired, ticagrelor should be discontinued 7 days prior to surgery.
Patients with prior ischemic stroke: Acute coronary syndromes (ACS) patients with prior ischemic stroke can be treated with ticagrelor for up to 12 months. Patients with history of myocardial infarction (MI) with prior ischemic stroke were not included. Therefore, in the absence of data, treatment beyond one year is not recommended in these patients.
Patients at risk of bradycardia events: Due to the limited clinical experience, ticagrelor should be used with caution in these patients.
In addition, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia. However, no evidence of clinically significant adverse reactions was observed after concomitant administration with one or more medicinal products known to induce bradycardia (e.g., 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin).
Creatinine elevations: Creatinine levels may increase during treatment with ticagrelor. The mechanism has not been elucidated. Renal function should be checked according to routine medical practice. In patients with acute coronary syndromes (ACS), it is recommended that renal function is also checked one month after initiating the treatment with ticagrelor, paying special attention to patients ≥75 years, patients with moderate/severe renal impairment, and those receiving concomitant treatment with an angiotensin receptor blocker (ARB).
Uric acid increase: Hyperuricemia may occur during treatment with ticagrelor. Caution is advised in patients with history of hyperuricemia or gouty arthritis. As a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged.
Other: Coadministration of ticagrelor and high maintenance dose acetylsalicylic acid (>300 mg) is not recommended.
Premature discontinuation: Premature discontinuation with any antiplatelet therapy, including ticagrelor, could result in an increased risk of cardiovascular (CV) death or myocardial infarction (MI) due to the patient's underlying disease. Therefore, premature discontinuation of treatment should be avoided.
Hepatic impairment: Use of ticagrelor is contraindicated in patients with severe hepatic impairment.
There is limited experience with ticagrelor in patients with moderate hepatic impairment. Therefore, caution is advised in these patients. Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.
Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Hence, ticagrelor is contraindicated for use in patients with severe hepatic impairment and its use should be considered carefully in patients with moderate hepatic impairment. No dosage adjustment is needed in patients with mild hepatic impairment (see Contraindications).
Renal impairment: No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied.
Use in Pregnancy: Pregnancy category: C.
There are no adequate and well-controlled studies of ticagrelor use in pregnant women. Ticagrelor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in Lactation: It is not known whether ticagrelor or its active metabolites are excreted in human 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 drug.
Use in Children: The safety and effectiveness of ticagrelor in pediatric patients have not been established.
Use in Elderly: No overall differences in safety or effectiveness were observed between these patients and younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
Use In Pregnancy & Lactation
Pregnancy: Pregnancy category: C.
There are no adequate and well-controlled studies of ticagrelor use in pregnant women. Ticagrelor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: It is not known whether ticagrelor or its active metabolites are excreted in human 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 drug.
Adverse Reactions
The following adverse reactions are also discussed elsewhere in the monograph: Bleeding (see Precautions): Major bleeding: Fatal/life-threatening: Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dl; transfusion of 4 or more units (whole blood or packed red blood cells (PRBCs)) for bleeding.
Other: Any one of the following: significantly disabling (e.g., intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dl; transfusion of 2-3 units (whole blood or PRBCs) for bleeding.
Minor bleeding: Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing).
Minimal bleeding: All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or treatment.
Dyspnea: Includes dyspnea exertional, dyspnea at rest, nocturnal dyspnea, dyspnea paroxysmal nocturnal (see Precautions).
The other common adverse reactions: Headache; Cough; Dizziness; Nausea; Atrial fibrillation; Hypertension; Non-cardiac chest pain; Diarrhea; Back pain; Hypotension; Fatigue; Chest pain; Bradycardia; Immune system disorders: hypersensitivity reactions including angioedema (see Contraindications); Skin and subcutaneous tissue disorders: rash; Gynecomastia and other sex-hormonal adverse reactions, including sex organ malignancies; Laboratory abnormalities: serum uric acid and serum creatinine levels increased.
Adverse reactions by frequency and system organ class: Neoplasm benign, malignant, and unspecified (including cyst and polyps): Uncommon: tumor bleedings (e.g., bleeding from bladder cancer, gastric cancer, colon cancer).
Blood and lymphatic system disorders: Very common: blood disorder bleedings (e.g., increased tendency to bruise, spontaneous hematoma, hemorrhagic diathesis).
Immune system disorders: Uncommon: hypersensitivity including angioedema.
Metabolism and nutrition disorders: Very common: hyperuricemia (uric acid increases to >upper limit of normal from baseline below or within reference range).
Common: gout/gouty arthritis.
Psychiatric disorders: Uncommon: confusion.
Nervous system disorders: Common: dizziness, syncope, headache.
Uncommon: intracranial hemorrhage.
Eye disorders: Uncommon: eye hemorrhage (e.g., conjunctival, retinal, intraocular bleeding).
Ear and labyrinth disorders: Common: vertigo.
Uncommon: ear hemorrhage. Vascular disorders Common: hypotension.
Respiratory, thoracic, and mediastinal disorders: Very common: dyspnea.
Common: respiratory system bleedings (e.g., epistaxis, hemoptysis).
Gastrointestinal disorders: Common: gastrointestinal hemorrhage (e.g., gingival bleeding, rectal hemorrhage, gastric ulcer hemorrhage), diarrhea, nausea, dyspepsia, constipation.
Uncommon: retroperitoneal hemorrhage.
Skin and subcutaneous tissue disorders: Common: subcutaneous or dermal bleeding (e.g., ecchymosis, skin hemorrhage, petechiae), rash, pruritus.
Musculoskeletal connective tissue and bone: Uncommon: muscular bleedings (e.g., hemarthrosis, muscle hemorrhage).
Renal and urinary disorders: Common: urinary tract bleeding (e.g., hematuria, cystitis hemorrhagic).
Reproductive system and breast disorders: Uncommon: reproductive system bleedings (e.g., vaginal hemorrhage, hematospermia, postmenopausal hemorrhage).
Investigations: Common: blood creatinine increased (creatinine increases of >50% from baseline).
Injury, poisoning, and procedural complications: Common: postprocedural hemorrhage, traumatic bleedings (e.g., confusion, traumatic hematoma, traumatic hemorrhage).
Drug Interactions
Effects of other drugs: Ticagrelor is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5.
Ticagrelor is also a P-glycoprotein (P-gp) substrate.
CYP3A inhibitors: Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin) (see Precautions).
CYP3A inducers: Avoid use with potent inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine, and phenobarbital) (see Precautions).
Aspirin: Use of ticagrelor with aspirin maintenance doses above 100 mg reduced the effectiveness of ticagrelor (see Precautions).
Effects of ticagrelor on other drugs: Ticagrelor is an inhibitor of CYP3A4/5 and the P-glycoprotein transporter.
Simvastatin, lovastatin: Ticagrelor 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: Ticagrelor can be administered with unfractionated or low-molecular-weight heparin, GPIIb/IIIa inhibitors, proton pump inhibitors, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers.
Ciclosporin (P-gp and CYP3A inhibitor): Coadministration of ciclosporin (600 mg) with ticagrelor increased ticagrelor Cmax and AUC equal to 2.3 fold and 2.8 fold, respectively. The AUC of the active metabolite was increased by 32% and Cmax was decreased by 15% in the presence of ciclosporin. No data are available on concomitant use of ticagrelor with other active substances that also are potent P-gp inhibitors and moderate CYP3A4 inhibitors (e.g., verapamil, quinidine) that also may increase ticagrelor exposure. If the association cannot be avoided, their concomitant use should be made with caution.
Oral contraceptives: Coadministration of ticagrelor and levonorgestrel and ethinyl estradiol increased ethinyl estradiol exposure approximately 20% but did not alter the pharmacokinetics of levonorgestrel. No clinically relevant effect on oral contraceptive efficacy is expected when levonorgestrel and ethinyl estradiol are coadministered with ticagrelor.
Medicinal products known to induce bradycardia: Due to observations of mostly asymptomatic ventricular pauses and bradycardia, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia. However, no evidence of clinically significant adverse reactions was observed after concomitant administration with one or more medicinal products known to induce bradycardia (e.g., 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin).
Others: Coadministration of ticagrelor with heparin, enoxaparin, and acetylsalicylic acid or desmopressin did not have any effect on the pharmacokinetics of ticagrelor or the active metabolite or on ADP induced platelet aggregation compared with ticagrelor alone. If clinically indicated, medicinal products that alter hemostasis should be used with caution in combination with ticagrelor. A 2 fold increase of ticagrelor exposure was observed after daily consumption of large quantities of grapefruit juice (3 x 200 ml). This magnitude of increased exposure is not expected to be clinically relevant to most patients.
Storage
Store at temperature below 30°C.
ATC Classification
B01AC24 - ticagrelor ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.
Presentation/Packing
FC tab 90 mg x 3 x 10's.
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