TICAGRELOR- ticagrelor_tablet, film coated

Ticagrelor and its major metabolite reversibly interact with the platelet P2Y 12 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 muM ADP as the platelet aggregation agonist. 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 Ticagrelor Clopidogrel Placebo Transitioning from clopidogrel to ticagrelor tablets resulted in an absolute IPA increase of 26. 4% and from ticagrelor tablets to clopidogrel resulted in an absolute IPA decrease of 24. Patients can be transitioned from clopidogrel to ticagrelor tablets without interruption of antiplatelet effect [see Dosage and Administration (2) Figure 3 Figure 4 Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers. Absorption max max max max max max Distribution Metabolism Excretion 1/2 Specific Populations Patients with End-Stage Renal Disease on Hemodialysis max Figure 7 - Impact of intrinsic factors on the pharmacokinetics of ticagrelor Effects of Other Drugs on Ticagrelor Tablets max Figure 8 - Effect of co-administered drugs on the pharmacokinetics of ticagrelor *See Dosage and Administration ( 2 Effects of Ticagrelor Tablets on Other Drugs Figure 9 - Impact of ticagrelor tablets on the pharmacokinetics of co-administered drugs 21 Figure 6 Figure 7 In a genetic substudy cohort of PLATO, the rate of thrombotic CV events in the ticagrelor tablets arm did not depend on CYP2C19 loss of function status.

Ticagrelor tablets are a P2Y 12 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. 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). 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). 3 Ticagrelor tablets are indicated to reduce the rate of cardiovascular (CV) death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction (MI). Ticagrelor tablets also reduce the rate of stent thrombosis in patients who have been stented for treatment of ACS [see Clinical Studies ( 14. 1 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 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.

ACS or History of MI 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. 1 Patients with CAD and No Prior Stroke or MI Administer 60 mg ticagrelor tablets twice daily. 2 Acute Ischemic Stroke Initiate treatment with 180 mg oral loading dose of ticagrelor tablets then continue treatment with 90 mg twice daily for up to 30 days. 3 Use ticagrelor tablets with a daily maintenance dose of aspirin of 75-100 mg. 2 Initiate treatment with a 180 mg loading dose of ticagrelor tablets. Administer 90 mg of ticagrelor tablets twice daily during the first year after an ACS event. After one year, administer 60 mg of ticagrelor tablets twice daily. [see Warnings and Precautions ( 5. 2 14 Administer 60 mg of ticagrelor tablets twice daily. For all patients with ACS [see Dosage and Administration ( 2. 1 [see Warnings and Precautions ( 5. 2 14 Initiate treatment with a 180 mg loading dose of ticagrelor tablets and then continue with 90 mg twice daily for up to 30 days. The treatment effect accrued early in the course of therapy [see Clinical Studies ( 14. 3 [see Warnings and Precautions ( 5. 2 14 A patient who misses a dose of ticagrelor tablets should take one tablet (their next dose) at its scheduled time. [see Clinical Pharmacology ( 12.

The following adverse reactions are also discussed elsewhere in the labeling: Bleeding [see Warnings and Precautions ( 5. 1 Dyspnea [see Warnings and Precautions ( 5. 3 Most common adverse reactions (>5%) are bleeding and dyspnea. 1 To report SUSPECTED ADVERSE REACTIONS, contact Hisun Pharmaceuticals USA, Inc. at 1-855-554-4786 or FDA at 1-800-FDA-1088 or www. gov/medwatch Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Ticagrelor tablets have been evaluated for safety in more than 58,000 patients. Bleeding in PLATO (Reduction in risk of thrombotic events in ACS) Figure 1 is a plot of time to the first non-CABG major bleeding event. Figure 1 - Kaplan-Meier estimate of time to first non-CABG PLATO-defined major bleeding event (PLATO) Frequency of bleeding in PLATO is summarized in Tables 1 and 2. About half of the non-CABG major bleeding events were in the first 30 days. Table 1 - Non-CABG related bleeds (PLATO) Ticagrelor Tablets* N=9235 Clopidogrel N=9186 n (%) patients with event n (%) patients with event PLATO Major + Minor 713 (7. 2) Major 362 (3. 3) Fatal/Life-threatening 171 (1. 6) Fatal 15 (0. 2) Intracranial hemorrhage (Fatal/Life-threatening) 26 (0. 2) PLATO Minor bleed PLATO Major bleed PLATO Major bleed, fatal/life-threatening Fatal * 90 mg BID No baseline demographic factor altered the relative risk of bleeding with ticagrelor tablets compared to clopidogrel. In PLATO, 1584 patients underwent CABG surgery. The percentages of those patients who bled are shown in Figure 2 and Table 2. Figure 2 - Major fatal/life-threatening CABG-related bleeding by days from last dose of study drug to CABG procedure (PLATO) X-axis is days from last dose of study drug prior to CABG. The PLATO protocol recommended a procedure for withholding study drug prior to CABG or other major surgery without unblinding. If surgery was elective or non-urgent, study drug was interrupted temporarily, as follows: If local practice was to allow antiplatelet effects to dissipate before surgery, capsules (blinded clopidogrel) were withheld 5 days before surgery and tablets (blinded ticagrelor) were withheld for a minimum of 24 hours and a maximum of 72 hours before surgery. If local practice was to perform surgery without waiting for dissipation of antiplatelet effects capsules and tablets were withheld 24 hours prior to surgery and use of aprotinin or other haemostatic agents was allowed. If local practice was to use IPA monitoring to determine when surgery could be performed both the capsules and tablets were withheld at the same time and the usual monitoring procedures followed. T Ticagrelor; C Clopidogrel. Table 2 - CABG-related bleeding (PLATO) Ticagrelor Tablets* N=770 Clopidogrel N=814 n (%) patients with event n (%) patients with event PLATO Total Major 626 (81. 8) Fatal/Life-threatening 337 (43. 0) Fatal 6 (0. 9) PLATO Major bleed PLATO Major bleed, fatal/life-threatening * 90 mg BID When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of ticagrelor tablets treated patients and 79% on clopidogrel. Other Adverse Reactions in PLATO Adverse reactions that occurred at a rate of 4% or more in PLATO are shown in Table 3. Table 3 - Percentage of patients reporting non-hemorrhagic adverse reactions at least 4% or more in either group and more frequently on ticagrelor tablets (PLATO) Ticagrelor Tablets* N=9235 Clopidogrel N=9186 Dyspnea 13. 8 Dizziness 4. 8 * 90 mg BID Bleeding in PEGASUS (Secondary Prevention in Patients with a History of Myocardial Infarction) Overall outcome of bleeding events in the PEGASUS study are shown in Table 4. Table 4 - Bleeding events (PEGASUS) Ticagrelor Tablets* N=6958 Placebo N=6996 Events / 1000 patient years Events / 1000 patient years TIMI Major 8 3 Fatal 1 1 Intracranial hemorrhage 2 1 TIMI Major or Minor 11 5 TIMI Major Fatal TIMI Minor * 60 mg BID The bleeding profile of ticagrelor tablets 60 mg compared to aspirin alone was consistent across multiple pre-defined subgroups (e. , by age, gender, weight, race, geographic region, concurrent conditions, concomitant therapy, stent, and medical history) for TIMI Major and TIMI Major or Minor bleeding events. Other Adverse Reactions in PEGASUS Adverse reactions that occurred in PEGASUS at rates of 3% or more are shown in Table 5. Table 5 - Non-hemorrhagic adverse reactions reported in >3. 0% of patients in the ticagrelor 60 mg treatment group (PEGASUS) Ticagrelor Tablets* N=6958 Placebo N=6996 Dyspnea 14. 5% Dizziness 4. 1% Diarrhea 3. 5% * 60 mg BID Bleeding in THEMIS (Prevention of major CV events in patients with CAD and Type 2 Diabetes Mellitus) The Kaplan-Meier curve of time to first TIMI Major bleeding event is presented in Figure 3. Figure 3 - Time to first TIMI Major bleeding event (THEMIS) T = Ticagrelor; P = Placebo; N = Number of patients The bleeding events in THEMIS are shown below in Table 6. Table 6 en dash Bleeding events (THEMIS) Ticagrelor Tablets Placebo Events / 1000 patient years Events / 1000 patient years TIMI Major 9 4 TIMI Major or Minor 12 5 TIMI Major or Minor or Requiring medical attention 46 18 Fatal bleeding 1 0 Intracranial hemorrhage 3 2 Bleeding in THALES (Reduction in risk of stroke in patients with acute ischemic stroke or TIA) Figure 4 - Time course of GUSTO severe bleeding events KM%: Kaplan-Meier percentage evaluated at Day 30; T = Ticagrelor; P = placebo; N = Number of patients GUSTO Severe Intracranial bleeding and fatal bleeding in THALES: Bradycardia In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with ticagrelor tablets (6. 0%) than with clopidogrel (3. 5%) in the acute phase; rates were 2. 6%, respectively, after 1 month. PLATO, PEGASUS, THEMIS and THALES excluded patients at increased risk of bradycardic events (e. , patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker). Lab abnormalities Serum Uric Acid: In PLATO, serum uric acid levels increased approximately 0. 6 mg/dL from baseline on ticagrelor tablets 90 mg and approximately 0. 2 mg/dL on clopidogrel. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0. 6% in each group). In PEGASUS, serum uric acid levels increased approximately 0. 2 mg/dL from baseline on ticagrelor tablets 60 mg and no elevation was observed on aspirin alone. Gout occurred more commonly in patients on ticagrelor tablets than in patients on aspirin alone (1. Mean serum uric acid concentrations decreased after treatment was stopped. Serum Creatinine: In PLATO, a >50% increase in serum creatinine levels was observed in 7. 4% of patients receiving ticagrelor tablets 90 mg compared to 5. 9% of patients receiving clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria. In PEGASUS, serum creatinine concentration increased by >50% in approximately 4% of patients receiving ticagrelor tablets 60 mg, similar to aspirin alone. The frequency of renal related adverse events was similar for ticagrelor and aspirin alone regardless of age and baseline renal function. Figure 1 Figure 2 15 16 The following adverse reactions have been identified during post-approval use of ticagrelor tablets. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Immune system disorders [see Contraindications ( 4. 3 Respiratory Disorders: Skin and subcutaneous tissue disorders.

History of intracranial hemorrhage ( 4. 1 Active pathological bleeding ( 4. 2 Hypersensitivity to ticagrelor or any component of the product ( 4. 3 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. 2 Ticagrelor tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions ( 5. 1 Ticagrelor tablets are contraindicated in patients with hypersensitivity (e. , angioedema) to ticagrelor or any component of the product.

Lactation: Breastfeeding not recommended ( 8. 2 Risk Summary Data Animal Data 2 2 2 2 2 2 Risk Summary The safety and effectiveness of ticagrelor tablets have not been established in pediatric patients. Effectiveness was not demonstrated in an adequate and well-controlled study conducted in 101 ticagrelor tablets-treated pediatric patients, aged 2 to <18 for reducing the rate of vaso-occlusive crises in sickle cell disease. About half of the patients in PLATO, PEGASUS, THEMIS, and THALES were >=65 years of age and at least 15% were >=75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients. Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Avoid use of ticagrelor tablets in patients with severe hepatic impairment. There is limited experience with ticagrelor tablets 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 and Precautions ( 5. 3) No dosage adjustment is needed in patients with renal impairment. [see Clinical Pharmacology (12. 3) Patients with End-Stage Renal Disease on dialysis [see Clinical Pharmacology ( 12.

Avoid use with strong CYP3A inhibitors or CYP3A inducers. 2 Opioids: Decreased exposure to ticagrelor. Consider use of parenteral anti-platelet agent. 4 Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse effects. 5 Monitor digoxin levels with initiation of or any change in ticagrelor tablets. 6 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. , ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin) [see Clinical Pharmacology (12. 3) Strong CYP3A inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor. Avoid use with strong inducers of CYP3A (e. , rifampin, phenytoin, carbamazepine and phenobarbital) [see Clinical Pharmacology (12. 3) Use of ticagrelor tablets with aspirin maintenance doses above 100 mg reduced the effectiveness of ticagrelor tablets [see Warnings and Precautions ( 5. 1 As with other oral P2Y 12 [see Clinical Pharmacology (12. 3) Ticagrelor tablets increase serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg [see Clinical Pharmacology (12. 3) Ticagrelor tablets inhibit the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in ticagrelor tablets therapy [see Clinical Pharmacology (12.

OVERDOSAGE
There is currently no known treatment to reverse the effects of ticagrelor tablets, 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 measures should be taken. Platelet transfusion did not reverse the antiplatelet effect of ticagrelor tablets 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.
NONCLINICAL TOXICOLOGY
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 MRHD 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 MRHD 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 MRHD on the basis of AUC). Doses of >=10 mg/kg/day given to female rats caused an increased incidence of irregular duration estrus cycles (1.5-fold the MRHD based on AUC).
CLINICAL STUDIES
PLATO Patients who had already been treated with clopidogrel could be enrolled and randomized to either study treatment. Patients with previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. Patients could be included whether there was intent to manage the ACS medically or invasively, but patient randomization was not stratified by this intent. All patients randomized to ticagrelor tablets received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. Patients in the clopidogrel arm were treated with an initial loading dose of clopidogrel 300 mg, if clopidogrel therapy had not already been given. Patients undergoing PCI could receive an additional 300 mg of clopidogrel at investigator discretion. A daily maintenance dose of aspirin 75-100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local judgment. Patients were treated for at least 6 months and for up to 12 months. PLATO patients were predominantly male (72%) and Caucasian (92%). About 43% of patients were >65 years and 15% were >75 years. Median exposure to study drug was 276 days. About half of the patients received pre-study clopidogrel and about 99% of the patients received aspirin at some time during PLATO. About 35% of patients were receiving a statin at baseline and 93% received a statin sometime during PLATO. Table 7 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. Separate secondary endpoint analyses are shown for the overall occurrence of CV death, MI, and stroke and overall mortality. Table 7 - Patients with outcome events (KM%) (PLATO) Ticagrelor Tablets * N=9333 Clopidogrel N=9291 Hazard Ratio (95% CI) p Events / 1000 patient years Events / 1000 patient years Composite of CV death, MI, or stroke 111 131 0. 0003 CV death 32 43 0. 74 Non-fatal MI 64 76 0. 84 Non-fatal stroke 15 12 1. 24 Secondary endpoints dagger CV death 45 57 0. 0013 MI double dagger 65 76 0. 0045 Stroke double dagger 16 14 1. 22 All-cause mortality 51 65 0. 0003 * dagger double dagger The Kaplan-Meier curve (Figure 10) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke in the overall study. Figure 10 - Time to first occurrence of CV death, MI, or stroke (PLATO) The curves separate by 30 days [relative risk reduction (RRR) 12%] and continue to diverge throughout the 12-month treatment period (RRR 16%). Among 11,289 patients with PCI receiving any stent during PLATO, there was a lower risk of stent thrombosis (1. 3% for adjudicated definite) than with clopidogrel (1. 67, 95% CI 0. The results were similar for drug-eluting and bare metal stents. A wide range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcome. Some of these are shown in Figure 11. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Most of the analyses show effects consistent with the overall results, but there are two exceptions: a finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin. These are considered further below. Most of the characteristics shown are baseline characteristics, but some reflect post-randomization determinations (e. , aspirin maintenance dose, use of PCI). Figure 11 - Subgroup analyses of (PLATO) Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Regional Differences Results in the rest of the world compared to effects in North America (US and Canada) show a smaller effect in North America, numerically inferior to the control and driven by the US subset. The statistical test for the US/non-US comparison is statistically significant (p=0. 009), and the same trend is present for both CV death and non-fatal MI. The individual results and nominal p-values, like all subset analyses, need cautious interpretation, and they could represent chance findings. The consistency of the differences in both the CV mortality and non-fatal MI components, however, supports the possibility that the finding is reliable. A wide variety of baseline and procedural differences between the US and non-US (including intended invasive vs. planned medical management, use of GPIIb/IIIa inhibitors, use of drug eluting vs. bare-metal stents) were examined to see if they could account for regional differences, but with one exception, aspirin maintenance dose, these differences did not appear to lead to differences in outcome. Aspirin Dose The PLATO protocol left the choice of aspirin maintenance dose up to the investigator and use patterns were different in US sites from sites outside of the US. About 8% of non-US investigators administered aspirin doses above 100 mg, and about 2% administered doses above 300 mg. In the US, 57% of patients received doses above 100 mg and 54% received doses above 300 mg. Overall results favored ticagrelor tablets when used with low maintenance doses ( 100 mg) of aspirin, and results analyzed by aspirin dose were similar in the US and elsewhere. Figure 10 shows overall results by median aspirin dose. Figure 12 shows results by region and dose. Figure 12 - CV death, MI, stroke by maintenance aspirin dose in the US and outside the US (PLATO) Like any unplanned subset analysis, especially one where the characteristic is not a true baseline characteristic (but may be determined by usual investigator practice), the above analyses must be treated with caution. It is notable, however, that aspirin dose predicts outcome in both regions with a similar pattern, and that the pattern is similar for the two major components of the primary endpoint, CV death and non-fatal MI. Despite the need to treat such results cautiously, there appears to be good reason to restrict aspirin maintenance dosage accompanying ticagrelor to 100 mg. Higher doses do not have an established benefit in the ACS setting, and there is a strong suggestion that use of such doses reduces the effectiveness of ticagrelor tablets. PEGASUS Patients were eligible to participate if they were >=50 years old, with a history of MI 1 to 3 years prior to randomization, and had at least one of the following risk factors for thrombotic cardiovascular events: age >=65 years, diabetes mellitus requiring medication, at least one other prior MI, evidence of multivessel coronary artery disease, or creatinine clearance <60 mL/min. Patients could be randomized regardless of their prior ADP receptor blocker therapy or a lapse in therapy. Patients requiring or who were expected to require renal dialysis during the study were excluded. Patients with any previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. A small number of patients with a history of stroke were included. Based on information external to PEGASUS, 102 patients with a history of stroke (90 of whom received study drug) were terminated early and no further such patients were enrolled. Patients were treated for at least 12 months and up to 48 months with a median follow up time of 33 months. Patients were predominantly male (76%) Caucasian (87%) with a mean age of 65 years, and 99. 8% of patients received prior aspirin therapy. The Kaplan-Meier curve (Figure 13) shows time to first occurrence of the primary composite endpoint of CV death, nonfatal MI or non-fatal stroke. Figure 13 - Time to first occurrence of CV death, MI or stroke (PEGASUS) Both the 60 mg and 90 mg regimens of ticagrelor tablets in combination with aspirin were superior to aspirin alone in reducing the incidence of CV death, MI or stroke. The absolute risk reductions for ticagrelor tablets plus aspirin vs. aspirin alone were 1. 19% for the 60 and 90 mg regimens, respectively. Although the efficacy profiles of the two regimens were similar, the lower dose had lower risks of bleeding and dyspnea. Table 8 - Incidences of the primary composite endpoint, primary composite endpoint components, and secondary endpoints (PEGASUS) Ticagrelor Tablets * N=7045 Aspirin Alone N=7067 HR (95% CI) p Events / 1000 patient years Events / 1000 patient years Time to first CV death, MI, or stroke dagger 26 31 0. 0043 CV Death double dagger, section 9 11 0. 01) Myocardial infarction section 15 18 0. 98) Stroke section 5 7 0. 98) All-cause mortality double dagger 16 18 0. 04) CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; MI = Myocardial infarction; N = Number of patients. * dagger double dagger section In PEGASUS, the relative risk reduction (RRR) for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (16% RRR) were similar. Figure 14 - Subgroup analyses of ticagrelor 60 mg (PEGASUS) Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 THEMIS Table 9 en dash Primary composite endpoint, primary endpoint components, and secondary endpoints (THEMIS) Ticagrelor Tablets Placebo HR (95% CI) p Events / 1000 patient years Events / 1000 patient years Time to first CV death, MI, or stroke * 24 27 0. 04 CV death dagger 12 11 1. 18) Myocardial infarction dagger 9 11 0. 98) Stroke dagger 6 7 0. 99) Secondary endpoints CV death 12 11 1. 18) Myocardial infarction 9 11 0. 98) Ischemic stroke 5 6 0. 99) All-cause death 18 19 0. 10) CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; MI = Myocardial infarction. * dagger The Kaplan-Meier curve (Figure 15) shows time to first occurrence of the primary composite endpoint of CV death, MI, or stroke. Figure 15 - Time to First Occurrence of CV death, MI or Stroke (THEMIS) T = Ticagrelor; P = Placebo; N = Number of patients. Figure 16 en dashSubgroup analyses of ticagrelor (THEMIS) Note: The figure above presents effects in various subgroups all of which are baseline characteristics. 17 18 THALES 2 Ticagrelor tablets were superior to placebo in reducing the rate of the primary endpoint (composite of stroke and death), corresponding to a relative risk reduction (RRR) of 17% and an absolute risk reduction (ARR) of 1. 1% (Table 10). The effect was driven primarily by a significant reduction in the stroke component of the primary endpoint (19% RRR, 1. Table 10 - Incidences of the primary composite endpoint, primary composite endpoint components, and secondary endpoint (THALES) Ticagrelor Tablets Placebo HR (95% CI) p n (patients with event) KM% n (patients with event) KM% Time to first Stroke or Death 303 5. 015 Time to first Stroke * 284 5. 95) Time to Death * 36 0. 19) Secondary Endpoint Time to first Ischemic Stroke 276 5. 04 CI = Confidence interval; HR = Hazard ratio; KM = Kaplan-Meier percentage calculated at 30 days; N = Number of patients * Figure 17 en dash Time to First Occurrence of Stroke or Death (THALES) KM%: Kaplan-Meier percentage evaluated at Day 30; T=Ticagrelor; P=placebo; N=Number of patients Figure 18 en dash Subgroup analyses of ticagrelor 90 mg (THALES) Note: The figure above presents effects in various subgroups all of which are baseline characteristics and were pre-specified.
MEDICATION GUIDE
TICAGRELOR (tye-KA-grel-or) Tablets What is the most important information I should know about ticagrelor tablets? Ticagrelor tablets are used to lower your chance of having, or dying from, a heart attack or stroke. Ticagrelor tablets (and similar drugs) can cause bleeding that can be serious and sometimes lead to death. you may bruise and bleed more easily you are more likely to have nose bleeds it will take longer than usual for any bleeding to stop Call your doctor right away, if you have any of these signs or symptoms of bleeding while taking ticagrelor tablets: bleeding that is severe or that you cannot control pink, red or brown urine vomiting blood or your vomit looks like “coffee grounds” red or black stools (looks like tar) coughing up blood or blood clots Do not stop taking ticagrelor tablets without talking to the doctor who prescribes it for you. Your doctor may instruct you to stop taking ticagrelor tablets 5 days before surgery. This will help to decrease your risk of bleeding with your surgery or procedure. Your doctor should tell you when to start taking ticagrelor tablets again, as soon as possible after surgery. Taking ticagrelor tablets with aspirin Ticagrelor tablets are taken with aspirin. Talk to your doctor about the dose of aspirin that you should take with ticagrelor tablets. In most cases, you should not take a dose of aspirin higher than 100 mg daily because it can affect how well ticagrelor tablets work. Do not take doses of aspirin higher than what your doctor tells you to take. Tell your doctor if you take other medicines that contain aspirin, and do not take new over-the-counter medicines with aspirin in them. What are ticagrelor tablets? Ticagrelor tablets are a prescription medicine used to: decrease your risk of death, heart attack, and stroke in people with a blockage of blood flow to the heart (acute coronary syndrome or ACS) or a history of a heart attack. Ticagrelor tablets can also decrease your risk of blood clots in your stent in people who have received stents for the treatment of ACS. decrease your risk of a first heart attack or stroke in people who have a condition where the blood flow to the heart is decreased (coronary artery disease or CAD) who are at high risk for having a heart attack or stroke. decrease your risk of stroke in people who are having a stroke (acute ischemic stroke) or mini-stroke (transient ischemic attack or TIA). It is not known if ticagrelor tablets are safe and effective in children. Do not take ticagrelor tablets if you: have a history of bleeding in the brain are bleeding now are allergic to ticagrelor or any of the ingredients in ticagrelor tablets. See the end of this Medication Guide for a complete list of ingredients in ticagrelor tablets. Before taking ticagrelor tablets, tell your doctor about all of your medical conditions, if you: have had bleeding problems in the past have had any recent serious injury or surgery plan to have surgery or a dental procedure have a history of stomach ulcers or colon polyps have lung problems, such as COPD or asthma have liver problems have a history of stroke are pregnant or plan to become pregnant. It is not known if ticagrelor tablets will harm your unborn baby. You and your doctor should decide if you will take ticagrelor tablets. are breastfeeding or plan to breastfeed. It is not known if ticagrelor tablets pass into your breast milk. You and your doctor should decide if you will take ticagrelor tablets or breastfeed. You should not do both without talking with your doctor. Tell all of your doctors and dentists that you are taking ticagrelor tablets. They should talk to the doctor who prescribed ticagrelor tablets for you before you have any surgery or invasive procedure. Tell your doctor about all the medicines you take, Ticagrelor tablets may affect the way other Especially tell your doctor if you take: an HIV-AIDS medicine medicine for heart conditions or high blood pressure medicine for high blood cholesterol levels medicine used to control pain an anti-fungal medicine by mouth an antibiotic medicine an anti-seizure medicine a blood thinner medicine rifampin Ask your doctor or pharmacist if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I take ticagrelor tablets? Take ticagrelor tablets exactly as prescribed by your doctor. Your doctor will tell you how many ticagrelor tablets to take and when to take them. Take ticagrelor tablets with aspirin as directed by your doctor. You may take ticagrelor tablets with or without food. Take your doses of ticagrelor tablets around the same time every day. If you forget to take your scheduled dose of ticagrelor tablets, take your next dose at its scheduled time. Do not take 2 doses at the same time unless your doctor tells you to. If you take too much ticagrelor tablets or overdose, call your doctor or poison control center right away, or go to the nearest emergency room. If you are unable to swallow the tablet(s) whole, What are the possible side effects of ticagrelor tablets? Ticagrelor tablets can cause serious side effects, including: See “What is the most important information I should know about ticagrelor tablets?” Shortness of breath I rregular breathing. These are not all of the possible side effects of ticagrelor tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ticagrelor tablets? Store ticagrelor tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Keep ticagrelor tablets and all medicines out of the reach of children. General information about ticagrelor tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ticagrelor tablets for a condition for which it was not prescribed. Do not give ticagrelor tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about ticagrelor tablets that is written for health professionals. What are the ingredients in ticagrelor tablets? Active ingredient: ticagrelor Inactive ingredients: microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, hypromellose E5, polyethylene glycol 4000, colloidal silicon dioxide, magnesium stearate, hypromellose 2910, titanium dioxide, polyethylene glycol 400, ferric oxide yellow, ferric oxide red, and ferrosoferric oxide. Distributed by: Hisun Pharmaceuticals USA, Inc. For more information call 1-855-554-4786 or go to www.hisunusa.com. Revised: 03/2023

Hisun Pharmaceuticals USA, Inc.

TICAGRELOR- ticagrelor_tablet, film coated Product manual source documgent