Ticalor

Yellow, round, biconvex film coated tablets debossed with 'T' above '90' on one face and plain on other face.
Each film-coated tablet contains ticagrelor 90 mg.

Pharmacology: Pharmacodynamics: Ticagrelor, a member of the chemical class cyclopentyltriazolopyrimidines (CPTP), which is an oral, direct acting, selective and reversibly binding P2Y₁₂ receptor antagonist that prevents adenosine diphosphate (ADP)-mediated P2Y₁₂ dependent platelet activation and aggregation. Ticagrelor does not prevent ADP binding, but when bound to the P2Y₁₂ receptor prevents ADP-induced signal transduction. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function has been shown to reduce the risk of CV events such as death, MI or stroke.
Onset and Offset of Action: Onset of pharmacological effect as demonstrated by a mean inhibition of platelet aggregation (IPA) for ticagrelor is at 0.5 hours after 180 mg loading dose of about 41%, with the maximum IPA effect of 87.9% to 89.6% by 2-4 hours post dose. 90% of patients had final extent IPA >70% by 2 hours post dose. The high IPA effect of ticagrelor between 87%-89% was maintained between 2-8 hours.
Ticagrelor has a faster rate of offset of IPA as compared to clopidogrel as determined by the slope of offset from 4-72 hours after last dose. Median final extent IPA measured after the last dose of ticagrelor is approximately 20-30% higher for ticagrelor compared to clopidogrel.
Pharmacokinetics: Absorption: Absorption of ticagrelor is rapid with a median t_max of approximately 1.5 hours. The formation of the major circulating metabolite AR-C124910XX (also active) is rapid with a median t_max of approximately 2.5 hours. The C_max and AUC of ticagrelor and the active metabolite increased in an approximately proportional manner with dose over the dose range studied (30-1260 mg).
The mean absolute bioavailability of ticagrelor was estimated to be 36% (range 25.4% to 64.0%). Ingestion of a high-fat meal had no effect on ticagrelor C_max of the AUC of the active metabolite, but resulted in a 21% increase in ticagrelor AUC and 22% decrease in the active metabolite C_max. These small changes are considered of minimal clinical significance; therefore, ticagrelor can be given with or without food.
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 C_max within 80-125% for ticagrelor and the active metabolite). Initial exposure (0.5 and 1 hour post-dose) from crushed ticagrelor tablets mixed in water was higher compared to whole tablets, with a generally identical concentration profile thereafter (2 to 48 hours).
Distribution: The steady state volume of distribution of ticagrelor is 87.5 L. Ticagrelor and the active metabolite is extensively bound to human plasma protein (>99.0%).
Metabolism: CYP3A is the major enzyme responsible for ticagrelor metabolism and the formation of the active metabolite and their interactions with other CYP3A substrates ranges from activation through to inhibition. Ticagrelor and the active metabolite are weak P-glycoprotein inhibitors.
The major metabolite of ticagrelor, which is also active as assessed by in vitro binding to the platelet P2Y₁₂ ADP-receptor. The systemic exposure to the active metabolite is approximately 30-40% of that obtained for ticagrelor.
Excretion: The primary route of ticagrelor elimination is via hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in faeces, 26.5% 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 active metabolite is mostly via biliary secretion. The mean t_½ was approximately 6.9 hours (range 4.5-12.8 hours) for ticagrelor and 8.6 hours (range 6.5-12.8 hours) for the active metabolite.
Pharmacokinetics in Special Population: Elderly: Higher exposures to ticagrelor (approximately 60% for both C_max and AUC) and the active metabolite (approximately 50% for both C_max and AUC) were observed in elderly (≥65 years) subjects compared to younger subjects. These differences are not considered clinically significant.
Pediatric: Ticagrelor has not been evaluated in a pediatric population.
Sex: Higher exposures to ticagrelor (approximately 52% and 37% for C_max and AUC, respectively) and the active metabolite (approximately 50% for both C_max and AUC) were observed in women compared to men. These differences are not considered clinically significant.
Renal Impairment: Exposure to ticagrelor was approximately 20% lower and exposure to the active metabolite was approximately 17% higher in patients with severe renal impairment compared to subjects with normal renal function. The IPA effect of ticagrelor was similar between the two groups, however there was more variability observed in individual response in patients with severe renal impairment. No dosing adjustment is needed in patients with renal impairment. No information is available concerning treatment of patients on renal dialysis.
Hepatic Impairment: C_max and AUC for ticagrelor were 12% and 23% higher in patients with mild hepatic impairment compared to matched healthy subjects, respectively, however the IPA effect of ticagrelor was similar between the two groups. No dose adjustment is needed for patients with mild hepatic impairment. Ticagrelor has not been studied in patients with moderate or severe hepatic impairment.
Race: Patients of Asian descent have a 39% higher mean bioavailability compared to Caucasian patients. Patients self-identified as Black had an 18% lower bioavailability of ticagrelor compared to Caucasian patients. In clinical pharmacology studies, the exposure (C_max and AUC) ticagrelor in Japanese subjects was approximately 40% (20% after adjusting for body weight) higher compared to that in Caucasians.

Acute Coronary Syndromes (ACS): Prevention of thrombotic events (cardiovascular death, myocardial infarction and stroke) in 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).
Acute Ischemic Stroke: Reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale score ≤5) or high-risk transient ischemic attack (TIA).

Recommended Dose: In patients with 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. Treatment is recommended for at least 12 months unless discontinuation of Ticagrelor is clinically indicated.
In patients with Acute Ischemic Stroke or Transient Ischemic Attack, initiate Ticagrelor with a single 180 mg loading dose (two tablets of 90 mg) and then continue with 90 mg twice daily for 30 days.
Patients taking Ticagrelor should also take a daily low maintenance dose of acetylsalicylic acid (ASA) of 75-150 mg, unless specifically contraindicated. An initial loading dose of ASA is recommended for patients with ACS, acute ischemic stroke or TIA.
Missed Dose: A patient who misses a dose of ticagrelor should take one 90 mg tablet (their next dose) at its scheduled time.
Conversion from Clopidogrel to Ticagrelor: Physicians who desire to switch patients from clopidogrel to Ticagrelor should administer the first 90 mg dose of ticagrelor 24 hours following the last dose of clopidogrel.
Dosage in Special Populations: Pediatric patients: Safety and efficacy in children below the age of 18 have not been established.
Elderly patients: No dose adjustment is required.
Patients with renal impairment: No dose adjustment is necessary for patients with renal impairment. No information is available concerning treatment of patients on renal dialysis.
Patients with hepatic impairment: No dose adjustment is necessary for patients with mild hepatic impairment. Ticagrelor has not been studied in patients with moderate or severe hepatic impairment.
Mode of Administration: Orally administration, can be taken with or without food.
For patients who are unable to swallow the whole tablet, 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.

Overdose of ticagrelor may affect to gastrointestinal bleeding and significant adverse drug reactions should be monitored e.g. dyspnoea and ventricular pauses which has to be immediately rescued.
In the event of an overdose, observe for these potential adverse effects and consider ECG monitoring.
There is currently no known antidote to reverse the effects of ticagrelor, and ticagrelor is not expected to dialyzable. Treatment of overdose should follow 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.

Hypersensitivity to ticagrelor or any component of the formulation.
Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).
History of intracranial hemorrhage.
Severe hepatic impairment.

Reduced Efficacy with Higher Aspirin Dosage: Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor and should be avoided. After initial dose, use with aspirin 75-100 mg per day.
Bleeding: Like other antiplatelet agents, ticagrelor 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 receiving ticagrelor who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other invasive procedure, even if no overt manifestations of bleeding are present.
If possible, bleeding should be managed without discontinuing ticagrelor. Stopping ticagrelor increases the risk of subsequent cardiovascular events.
Ticagrelor should be used with caution in patients who are using medicinal products that may increase the risk of bleeding (e.g., non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics).
No data exist with ticagrelor regarding a hemostatic benefit of platelet transfusions; circulating ticagrelor may inhibit transfused platelets. Since coadministration of ticagrelor with desmopressin did not decrease template bleeding time, desmopressin is unlikely to be effective in managing clinical bleeding events.
Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa therapy may augment hemostasis. Ticagrelor may be resumed after the cause of bleeding has been identified and controlled.
Surgery: If a patient requires surgery, physicians should consider each patient's clinical profile as well as the benefits and risks of continued antiplatelet therapy for determining when discontinuation of ticagrelor treatment should occur.
Because of the reversible binding of ticagrelor, restoration of platelet aggregation occurs faster with ticagrelor compared to clopidogrel. A risk of bleeding complications may be reduced, e.g. in settings where antiplatelet therapy must be temporarily discontinued due to surgery or trauma.
Patients undergoing CABG, ticagrelor had a similar rate of major bleeds compared to clopidogrel at all days after stopping therapy except Day 1 where ticagrelor had a higher rate of major bleeding.
If a patient is to undergo elective surgery and antiplatelet effect is not desired, ticagrelor should be discontinued at least 5 days prior to surgery.
Patients with hepatic impairment: Caution is advised in patients with moderate hepatic impairment because ticagrelor has not been studied in these patients.
Ticagrelor is contraindicated in patients with severe hepatic impairment.
Patients at risk for bradycardic events: Due to observations of mostly asymptomatic ventricular pauses in an earlier clinical study, patients with an increased risk of bradycardic events (e.g. patients without a pacemaker who have sick sinus syndrome, 2^nd or 3^rd degree AV block or bradycardic-related syncope) were excluded from the main study evaluating the safety and efficacy of ticagrelor. Therefore, due to the limited clinical experience in these patients, caution is advised.
Dyspnoea: Dyspnoea, usually mild to moderate in intensity and often resolving without need for treatment discontinuation, is reported in patients treated with ticagrelor (approximately 13.8%). The mechanism has not yet been elucidated, if a patient reports new, prolonged or worsened dyspnoea this should be investigated fully and if not tolerated, treatment with ticagrelor should be stopped.
Other: Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir), as co-administration may lead to a substantial increase in exposure to ticagrelor.
Discontinuation of Ticagrelor: Patients who require discontinuation of ticagrelor are at increased risk for cardiac events. Premature discontinuation of treatment should be avoided. If ticagrelor must be temporarily stopped due to an adverse event(s), should be re-initiated as soon as possible when the benefits outweigh the risks of the adverse event or when the adverse event has come to resolution.

No clinical study has been conducted in pregnant or lactating women.
Pregnancy: There are no or limited amount of clinical data on exposure to ticagrelor during pregnancy.
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Ticagrelor had no effect on male or female fertility.
Because animal reproduction studies are not always predictive of a human response, ticagrelor should be used during pregnancy only if the potential benefit to the mother justifies any potential risk to the foetus.
Lactation: The use of ticagrelor during breastfeeding is not recommended because it is not known whether this medicinal product is excreted in human milk. Studies in rats have shown that ticagrelor and active metabolites are excreted in the milk.

The safety of ticagrelor in patients with acute coronary syndromes (UA, NSTMI and STEMI) was evaluated in a single large phase 3 study (PLATO [Platelet Inhibition and Patient Outcomes] study) which compared patients treated with ticagrelor (loading dose of 180 mg of ticagrelor and a maintenance dose of 90 mg bid) to patients treated with clopidogrel (300-600 mg loading dose followed by 75 mg once daily maintenance dose) both given in combination with acetylsalicylic acid (aspirin) and other standard therapies.
The most commonly reported adverse events in patients treated with ticagrelor were bleedings and dyspnoea and these events occurred at higher rates than in the clopidogrel treatment group. During the treatment period, the ticagrelor group had a higher incidence of discontinuation due to adverse events than clopidogrel (7.4% vs 5.4%).
Adverse reactions are classified according to frequency and System Organ Class (SOC). Frequency categories are defined according to the following conventions: Very common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1,000, <1/100); Rare (≥1/10,000, <1/1,000); Very rare (≥1/10,000, <1/1,000). (See table.)

Click on icon to see table/diagram/image

Pharmacokinetic interactions: Effects of Other Drugs on Ticagrelor: Drugs metabolized by CYP3A4: Ketoconazole (Strong CYP3A4 inhibitors): Co-administration of ketoconazole with ticagrelor increased ticagrelor C_max and AUC equal to 2.4-fold and 7.3-fold, respectively. The C_max and AUC of the active metabolite were reduced by 89% and 56% respectively. Other strong inhibitors of CYP3A4 (clarithromycin, nefazodone, ritonavir and atazanavir) would be expected to have similar effects and should not be given concomitantly with ticagrelor.
Diltiazem (moderate CYP3A4 inhibitors): Co-administration of ticagrelor and diltiazem increased the C_max of ticagrelor by 69% and AUC 174% and decreased the active metabolite C_max by 38% and AUC was unchanged. There was no effect of ticagrelor on diltiazem plasma levels. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, erythromycin, fluconazole and verapamil) can as well be co-administered with ticagrelor.
Rifampin and other CYP3A inducers: Co-administration of rifampin with ticagrelor decreased ticagrelor C_max and AUC by 73% and 86%, respectively. The C_max of the active metabolite was unchanged and the AUC was decreased by 46% respectively. Other CYP3A4 inducers (e.g. phenytoin, carbamazepine and phenobarbital) would be expected to decrease the exposure to ticagrelor as well and may result in reduced efficacy of ticagrelor.
Cyclosporine (PgP and CYP3A inhibitor): Co-administration of cyclosporine (600 mg) with ticagrelor increased ticagrelor C_max and AUC equal to 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite was increased by 32% and C_max was decreased by 15% in the presence of cyclosporine. There was no effect of ticagrelor on cyclosporine blood levels.
Others: Clinical pharmacology interaction studies showed that co-administration of ticagrelor with heparin, enoxaparin and aspirin did not have any effect on ticagrelor or the active metabolite plasma levels. Co-administration of ticagrelor and heparin had no effect on heparin based on activated partial thromboplastin (aPTT) and activated coagulation time (ACT) assays. Co-administration of ticagrelor and enoxaparin had no effect on enoxaparin based on factor Xa assay.
Effects of Ticagrelor on Other Drugs: Drugs metabolized by CYP3A4: Simvastatin: Co-administration of ticagrelor with simvastatin increased simvastatin C_max by 81% and AUC by 56% and increased simvastatin acid C_max by 64% and AUC by 52% with some individual increases equal to 2- to 3-fold. Consideration of the clinical significance should be given to the magnitude and range of changes on the exposure to patients requiring greater than 40 mg of simvastatin. An increase in simvastatin exposure may increase simvastatin-related adverse events (e.g. myopathy including rhabdomyolysis).
There was no effect of simvastatin on ticagrelor plasma levels. Ticagrelor may have similar effect on lovastatin, but is not expected to have a clinically meaningful effect on other statins.
Atorvastatin: Co-administration of atorvastatin and ticagrelor increased atorvastatin acid C_max by 23% and AUC by 36%. Similar increases in AUC and C_max were observed for all atorvastatin acid metabolites. These increases are not considered clinically significant.
Medicinal products metabolized by CYP2C9: Tolbutamide: Co-administration of ticagrelor with tolbutamide resulted in no change in the plasma levels of either drug, which suggest that ticagrelor is not a CYP2C9 inhibitor and unlikely to alter the CYP2C9 mediated metabolism of drugs like warfarin and tolbutamide.
Oral contraceptives: Co-administration 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 co-administered with ticagrelor.
Digoxin (PgP substrate): Concomitant administration of ticagrelor increased the digoxin C_max by 75% and AUC by 28%. Therefore, appropriate clinical and/or laboratory monitoring is recommended when giving narrow therapeutic index P-gp dependent drugs like digoxin concomitantly with ticagrelor.
Other concomitant therapy: In clinical studies, ticagrelor was commonly administered with aspirin, heparin, low molecular weight heparin, intravenous GpIIb/IIIa inhibitors, proton pump inhibitors, statins, beta-blockers, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers as needed for concomitant conditions. These studies did not produce any evidence of clinically significant adverse interactions.

Store below 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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