ticagrelor 60 MG Oral Tablet

1. INDICATIONS AND USAGE SECTION Ticagrelor tablets are a P2Y12 platelet inhibitor indicated to reduce the risk of cardiovascular (CV) death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. For at least the first 12 months following ACS, it is superior to clopidogrel. Ticagrelor tablets also reduces the risk of stent thrombosis in patients who have been stented for treatment of ACS. ( 1.1 ) to reduce the risk of a first MI or stroke in patients with coronary artery disease (CAD) at high risk for such events. While use is not limited to this setting, the efficacy of ticagrelor tablets was established in a population with type 2 diabetes mellitus (T2DM). ( 1.2 ) to reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale score ≤5) or high-risk transient ischemic attack (TIA). ( 1.3 ) 1.1 Acute Coronary Syndrome or a History of Myocardial Infarction Ticagrelor tablets are indicated to reduce the risk of cardiovascular (CV) death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. For at least the first 12 months following ACS, it is superior to clopidogrel. Ticagrelor tablets also reduces the risk of stent thrombosis in patients who have been stented for treatment of ACS [see Clinical Studies ( 14.1 )]. 1.2 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction Ticagrelor tablets are indicated to reduce the risk of a first MI or stroke in patients with coronary artery disease (CAD) at high risk for such events [see Clinical Studies ( 14.2 )] . While use is not limited to this setting, the efficacy of ticagrelor tablets was established in a population with type 2 diabetes mellitus (T2DM). 1.3 Acute Ischemic Stroke or Transient Ischemic Attack (TIA) Ticagrelor tablets are indicated to reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale score ≤5) or high-risk transient ischemic attack (TIA) [see Clinical Studies ( 14.3 )] .

DOSAGE AND ADMINISTRATION • ACS or History of MI o Initiate treatment with 180 mg oral loading dose of ticagrelor tablets. Then administer 90 mg twice daily during the first year. After one year, administer 60 mg twice daily. (2.2) • Patients with CAD and No Prior Stroke or MI o Administer 60 mg ticagrelor tablets twice daily. (2.3) • Acute Ischemic Stroke o Initiate treatment with a 180 mg loading dose of ticagrelor tablets then continue with 90 mg twice daily for up to 30 days. (2.4) Use ticagrelor tablets with a daily maintenance dose of aspirin of 75 to 100 mg. (2) However, in patients who have undergone PCI, consider single antiplatelet therapy with ticagrelor tablets based on the evolving risk for thrombotic versus bleeding events. (2.2) 2.1 General Instructions Advise patients who miss a dose of ticagrelor tablet to take their next dose at its scheduled time. 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) [see Clinical Pharmacology (12.3)]. Do not administer ticagrelor tablet with another oral P2Y12 platelet inhibitor. Avoid aspirin at doses higher than recommended [see Clinical Studies (14.1)]. 2.2 Acute Coronary Syndrome or a History of Myocardial Infarction Initiate treatment with a 180 mg loading dose of ticagrelor tablet. Administer the first 90 mg maintenance dose of ticagrelor tablet, 6 to 12 hours after the loading dose. Administer 90 mg of ticagrelor tablet twice daily during the first year after an ACS event. After one year, administer 60 mg of ticagrelor tablet twice daily. Initiate ticagrelor tablet with a daily maintenance dose of aspirin of 75 mg to 100 mg. However, in patients who have undergone percutaneous coronary intervention (PCI), consider single antiplatelet therapy with ticagrelor tablet based on the evolving risk for thrombotic versus bleeding events [see Warnings and Precautions (5.1) and Clinical Studies (14)]. 2.3 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction Administer 60 mg of ticagrelor tablet twice daily. Generally, use ticagrelor tablet with a daily maintenance dose of aspirin of 75 mg to 100 mg [see Clinical Studies (14)]. 2.4 Acute Ischemic Stroke or Transient Ischemic Attack (TIA) Initiate treatment with a 180 mg loading dose of ticagrelor tablet and then continue with 90 mg twice daily for up to 30 days. Administer the first maintenance dose 6 to 12 hours after the loading dose. Use ticagrelor tablet with a loading dose of aspirin (300 mg to 325 mg) and a daily maintenance dose of aspirin of 75 mg to 100 mg [see Warnings and Precautions (5.2) and Clinical Studies (14)].

WARNINGS AND PRECAUTIONS Dyspnea was reported more frequently with ticagrelor tablets than with control agents in clinical trials. Dyspnea from ticagrelor tablets are self-limiting. ( 5.3 ) Severe Hepatic Impairment: Likely increase in exposure to ticagrelor. ( 5.5 ) Laboratory Test Interference: False negative platelet functional test results have been reported for Heparin Induced Thrombocytopenia (HIT). Ticagrelor tablets are not expected to impact PF4 antibody testing for HIT.( 5.7 ) 5.1 Risk of Bleeding Drugs that inhibit platelet function including ticagrelor tablets increase the risk of bleeding [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )]. Patients treated for acute ischemic stroke or TIA Patients at NIHSS greater than 5 and patients receiving thrombolysis were excluded from THALES and use of ticagrelor tablets in such patients is not recommended. 5.2 Discontinuation of Ticagrelor Tablets in Patients Treated for Coronary Artery Disease Discontinuation of ticagrelor tablets will increase the risk of myocardial infarction, stroke, and death in patients being treated for coronary artery disease. If ticagrelor tablets 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 tablets for five days prior to surgery that has a major risk of bleeding. Resume ticagrelor tablets as soon as hemostasis is achieved. 5.3 Dyspnea In clinical trials, about 14% (PLATO and PEGASUS) to 21% (THEMIS) of patients treated with ticagrelor tablets developed dyspnea. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment but led to study drug discontinuation in 0.9% (PLATO), 1.0% (THALES), 4.3% (PEGASUS), and 6.9% (THEMIS) of patients. 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 patient develops new, prolonged, or worsened dyspnea that is determined to be related to ticagrelor tablets, no specific treatment is required; continue ticagrelor tablets without interruption if possible. In the case of intolerable dyspnea requiring discontinuation of ticagrelor tablets, consider prescribing another antiplatelet agent. 5.4 Bradyarrhythmias Ticagrelor can cause ventricular pauses [see Adverse Reactions ( 6.1 )]. Bradyarrhythmias including AV block have been reported in the postmarketing setting. Patients with a history of sick sinus syndrome, 2 nd or 3 rd degree AV block or bradycardia-related syncope not protected by a pacemaker were excluded from clinical studies and may be at increased risk of developing bradyarrhythmias with ticagrelor. 5.5 Severe Hepatic Impairment Avoid use of ticagrelor tablets in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor. There are no studies of ticagrelor tablets patients with severe hepatic impairment [see Clinical Pharmacology ( 12.3 )]. 5.6 Central Sleep Apnea Central sleep apnea (CSA) including Cheyne-Stokes respiration (CSR) has been reported in the post-marketing setting in patients taking ticagrelor, including recurrence or worsening of CSA/CSR following rechallenge. If central sleep apnea is suspected, consider further clinical assessment. 5.7 Laboratory Test Interferences False negative functional tests for Heparin Induced Thrombocytopenia (HIT) Ticagrelor tablets have been reported to cause false negative results in platelet functional tests (including the heparin-induced platelet aggregation (HIPA) assay) for patients with Heparin Induced Thrombocytopenia (HIT). This is related to inhibition of the P2Y 12 -receptor on the healthy donor platelets in the test by ticagrelor in the affected patient’s serum/plasma. Information on concomitant treatment with ticagrelor tablets are required for interpretation of HIT functional tests. Based on the mechanism of ticagrelor tablets interference, ticagrelor tablets are not expected to impact PF4 antibody testing for HIT.

CONTRAINDICATIONS • History of intracranial hemorrhage. ( 4.1 ) • Active pathological bleeding. ( 4.2 ) • Hypersensitivity to ticagrelor or any component of the product. ( 4.3 ) 4.1 History of Intracranial Hemorrhage Ticagrelor tablets are contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population [see Clinical Studies ( 14.1 ) ,( 14.2 )]. 4.2 Active Bleeding Ticagrelor tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions ( 5.1 ) and Adverse Reactions (6.1 )]. 4.3 Hypersensitivity Ticagrelor tablets are contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product.

12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ticagrelor and its major metabolite reversibly interact with the platelet P2Y 12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent. 12.2 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 μM 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. As shown in Figure 5, 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 μM ADP. As shown in Figure 6, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 6 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 or thrombotic risk track with IPA, for either ticagrelor or clopidogrel. Figure 5 – Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel Figure 6 – Mean inhibition of platelet aggregation (IPA) following 6 weeks on placebo, ticagrelor 90 mg twice daily, or clopidogrel 75 mg daily Transitioning from clopidogrel to ticagrelor resulted in an 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 ticagrelor without interruption of antiplatelet effect [see Dosage and Administration ( 2 )] . FIG_5. FIG_6. 12.3 Pharmacokinetics Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers. Absorption Ticagrelor tablets 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 C max , but resulted in a 21% increase in AUC. The C max 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 C max 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. Ticagrelor is a BCRP inhibitor. 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 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 in Figure 7. Effects are modest and do not require dose adjustment. Patients with End-Stage Renal Disease on Hemodialysis In 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 was administered immediately prior to dialysis showing that 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. Figure 7 – Impact of intrinsic factors on the pharmacokinetics of ticagrelor *Single dose of ticagrelor administered on a day without dialysis. **Ticagrelor has not been studied in patients with moderate or severe hepatic impairment. Effects of Other 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 in Figure 8 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. T max was delayed by 1-2 hours. Exposure of the active metabolite decreased to a 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. Figure 8 – Effect of co-administered drugs on the pharmacokinetics of ticagrelor *See Dosage and Administration ( 2 ) 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. In vitro metabolism studies demonstrate that ticagrelor is a BCRP inhibitor. 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, levonorgesterol, tolbutamide, digoxin and cyclosporine, see Figure 9. Figure 9 - Impact of ticagrelor on the pharmacokinetics of co-administered drugs *Similar increases in AUC and C max were observed for all metabolites **Monitor digoxin levels with initiation of or change in ticagrelor therapy FIG_7. FIG_8. FIG_9. 12.5 Pharmacogenomics In a genetic substudy cohort of PLATO, the rate of thrombotic CV events in the ticagrelor arm did not depend on CYP2C19 loss of function status.