Pink, round, biconvex, film coated tablet.
Ticalor contains Ticagrelor, a cyclopentyl triazolopyridine inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP-receptor. Chemically it is (1S,2S,3R,5S)-3-[7-(1R,2S)-2-(3,4 difluorophenyl) cyclopropyl] amino)-5-) propylthio)-3H-[1,2,3-triazol[4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1,2-diol. The empirical formula of ticagrelor C23H28F2N6O4S and its molecular weight is 522.57. Ticagrelor is crystalline powder with an aqueous solubility of approximately 10 ug/mL at room temperature.
Each tablet contains: Ticagrelor 90 mg.
Pharmacology: Mechanism of Action: Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.
Pharmacodynamics: The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6 week study examining both acute and chronic platelet inhibition effects in response to 20 uM ADP as the platelet aggregation agonist. The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. IPA was higher in the ticagrelor group at all time points. The maximum IPA effect of ticagrelor was reached at around 2 hours and was maintained for at least 8 hours. The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 uM ADP, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert shows that after 24 hours IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%) indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel after 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk of thrombotic risk with IPA for either ticagrelor or clopidogrel. Transitioning for clopidogrel to Ticalor resulted in absolute IPA increase of 26.4% and from ticagrelor to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to Ticalor without interruption of antiplatelet effect (see Dosage & Administration).
Pharmacokinetics: Ticagrelor demonstrates dose proportional pharmacokinetics. Which are similar in patients and healthy volunteers.
Absorption: Ticalor 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 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. Ticalor 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 2.0 hours (range 1.0-8.0) for AR-C124910XX.
Distribution: The steady state volume of distribution of ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%).
Metabolism: CYP3A4 is the 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 eliminations 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.
Specific Populations: The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented. Effects are modest and do not require dose adjustment. Patients with End-Stage Renal Disease on hemodialysis: AUC and Cmax of ticagrelor 90 mg administered on a day without dialysis were 38% and 51% higher respectively, compared to subjects with normal renal function. A similar increase in exposure was observed when ticagrelor is not dialyzable. Exposure of the active metabolite increased to a lesser extent. The IPA effect of ticagrelor was independent of dialysis in patients with end stage renal disease and similar to healthy adults with normal renal function.
Effects of their drugs on ticagrelor: CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. The effects of other drugs on the pharmacokinetics of ticagrelor are presented as change relative to ticagrelor given alone (test/reference). 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., cyclosporine) increase ticagrelor exposure. Co-administration of 5 mg intravenous morphine with 180 mg loading dose of ticagrelor decreased observed mean ticagrelor exposure by up to 25% in healthy adults and up to 36% in ACS patients undergoing PCI. Tmax was delayed by 1-2 hours. Exposure of the active metabolite decreased to as similar extent.
Morphine co-administration did not delay or decrease platelet inhibition in healthy adults. Mean platelet aggregation was higher up to 3 hours post loading dose in ACS patients co-administered with morphine. Co-administration of intravenous fentanyl with 180 mg loading dose of ticagrelor in ACS patients undergoing PCI resulted in similar effects on ticagrelor exposure and platelet inhibition.
Effects of ticagrelor on other drugs: In vitro metabolism studies demonstrate that 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. For specific in vivo effects on the pharmacokinetics of simvastatin, atorvastatin, ethinyl estradiol, levonorgestrel, tolbutamide, digoxin and cyclosporine.
Pharmacogenetics: In a genetic sub-study cohort of PLATO, the rate of thrombotic CV events in the Ticalor arm did not depend on CYP2C19 loss of function status.
Non Clinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Ticagrelor was not carcinogenic in the mouse at doses up to 250 mg/kg/day or in the male rat at doses up to 120 mg/kg/day (19 and 15 times the MHRD of 90 mg twice daily on the basis of AUC, respectively). Uterine carcinomas, uterine adenocarcinomas and hepatocellular adenomas were seen in female rats at doses of 180 mg/kg/day (29-fold the maximally recommended dose of 90 mg twice daily on the basis of AUC), whereas 60 mg/kg/day (8-fold the MHRD based on AUC) was not carcinogenic in female rats.
Mutagenesis: Ticagrelor did not demonstrate genotoxicity when tested in the Ames Bacterial mutagenicity test, mouse lymphoma assay and the rat micronucleus test. The active O-demethylated metabolite did not demonstrate genotoxicity in the Ames assay and mouse lymphoma assay.
Impairment of Fertility: Ticagrelor had no effect on male fertility at doses up to 180 mg/kg/day or on female fertility at doses up to 200 mg/kg/day (>15-fold the MHRD on the basis of AUC). Doses of ≥10 mg/kg/day given to female rats caused an increase incidence of irregular duration estrus cycle (1.5-fold the MHRD based on AUC).
Ticagrelor (Ticalor) 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. Ticalor also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.
Dosing in the management of ACS, initiate Ticalor treatment with a 180 mg loading dose. Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily. Do not administer Ticalor with another oral P2Y12 platelet inhibitor. Use Ticalor with a daily maintenance dose of aspirin of 75-100 mg (see Warnings and Precautions).
A patient who misses a dose of Ticalor should take one tablet (their next dose) at its scheduled time.
Administration for patients who are unable to swallow tablets whole, Ticalor tablets can be crushed, mixed with water and drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater).
There is currently no known treatment to reverse the effects of Ticalor, and ticagrelor is not dialyzable. Treatment of overdose should follow local standard medical practice. Bleeding is the expected pharmacologic effect of overdosing. If bleeding occurs, appropriate supportive measure should be taken. Platelet transfusion did not reverse the antiplatelet effect of Ticalor 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: Ticalor is contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population.
Active bleeding: Ticalor is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial haemorrhage (see Warnings, Precautions and Adverse Reactions).
Hypersensitivity: Ticalor is contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product.
Bleeding Risk: Ticalor, like the other antiplatelet agents, can cause significant, sometimes fatal bleeding (see Precautions and Adverse Reactions).
Do not use Ticalor in patients with active pathological bleeding or a history of intracranial haemorrhage (see Contraindications).
Do not start Ticalor in patients undergoing urgent coronary artery bypass graft surgery (CABG).
If possible, manage bleeding without discontinuing Ticalor. Stopping Ticalor increases the risk of subsequent cardiovascular events.
Aspirin dose and Ticalor effectiveness: Maintenance doses of aspirin above 100 mg reduce the effectiveness of Ticalor and should be avoided.
General Risk of Bleeding: Drugs that inhibit platelet function including Ticalor increase the risk of bleeding (see Adverse Reactions). If possible, manage bleeding without discontinuing Ticalor. Stopping Ticalor increases the risk of subsequent cardiovascular events (see Warnings, Precautions and Adverse Reactions).
Concomitant Aspirin Maintenance Dose: In PLATO, the use of Ticalor with maintenance dose of aspirin above 100 mg decreased the effectiveness of Ticalor. Therefore, after the initial loading dose of aspirin, use Ticalor with a maintenance dose of aspirin 75-100 mg (see Dosage & Administration).
Dyspnea: Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment, but led to study drug discontinuation in 0.9% of Ticalor and 0.1% of clopidogrel patients in PLATO and 4.3% of Ticalor 60 mg and 0.7% on aspirin alone patients in PEGASUS. In a substudy 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 patients develops new, prolonged, or worsened dyspnea that is determined to be related to Ticalor, no specific treatment is required; continue Ticalor without interruption if possible. In the case of intolerable dyspnea requiring discontinuation of Ticalor, consider prescribing another antiplatelet agent.
Discontinuation of Ticalor: Discontinuation of Ticalor will increase the risk of myocardial infarction, stroke, and death. If Ticalor must be temporarily discontinued (e.g., to treat bleeding or for significant surgery), restart it as soon as possible. When possible, interrupt therapy with Ticalor for five days prior to surgery that has a major risk of bleeding. Resume Ticalor as soon as hemostasis is achieved.
Bradyarrhythmias: Ticagrelor can cause ventricular pauses (see Adverse Reactions). Bradyarrhythmias including AV block have been reported in the postmarketing 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 PLATO and PEGASUS and may be at increased risk of developing bradyarrhythmias with ticagrelor.
Use in 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 Ticalor 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 (see Warnings, Precautions and Pharmacology: Pharmacokinetics under Actions).
Severe Hepatic Impairment: Avoid use of Ticalor 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 (see Pharmacology: Pharmacokinetics under Actions).
Use in Renal Impairment: No dosage adjustment is needed in patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Patients with end-stage renal disease on dialysis: Clinical efficacy and safety studies with ticagrelor did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, no clinically significant difference in concentrations of ticagrelor and its metabolite and platelet inhibition are expected compared to those observed in patients with normal renal function (see Pharmacology: Pharmacokinetics under Actions). It is known whether these concentrations will lead to similar reductions in risk of CV death, myocardial infarction or stroke or similar bleeding risk in patients with ESRD on dialysis as were seen in PLATO and PEGASUS.
Use in Children: The safety and effectiveness of Ticalor in pediatric patients have not been established.
Use in the Elderly: In PLATO AND PEGASUS, about half of 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.
Pregnancy: Risk Summary: Available data from case reports with Ticalor use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Ticagrelor given to pregnant rats and pregnant rabbits during organogenesis caused structural abnormalities in the offspring at maternal doses about 5 to 7 times the maximum recommended human dose (MHRD) based on body surface area. When ticagrelor was given to rats during late gestation and lactation, pup death and effects on pup growth were seen at approximately 10 times the MHRD. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. General population, in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively development of liver and skeleton was seen. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, foetuses exposed to the highest maternal doses of 63 mg/kg/day (6.8 times the MHRD on a 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 g/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 MHRD on a 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 MHRD on a mg/m2 basis).
Lactation: Risk summary: There are no data on the presence of ticagrelor or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Ticagrelor and its metabolites were present in rat milk at higher concentrations than in maternal plasma. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Breastfeeding is not recommended during treatment with Ticalor.
The following adverse reactions are also discussed elsewhere in the labelling: Bleeding (see Warnings and Precautions).
Dyspnea (see Warnings and Precautions).
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) (see Pharmacology: Pharmacokinetics under Actions).
Strong CYP3A Inducer: 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) (see Pharmacology: Pharmacokinetics under Actions).
Aspirin: Use of Ticalor with aspirin maintenance doses above 100 mg reduced the effectiveness of Ticalor (see Warnings and Precautions).
Opioids: As with other oral P2Y12 inhibitors, co-administration of opioid agonists delay 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.
Digoxin: Ticalor inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in ticagrelor therapy (see Pharmacology: Pharmacokinetics under Actions).
Store at temperatures not exceeding 30°C.
Store in dry places, away from light.
B01AC24 - ticagrelor ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.
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