ticagrelor

Ticagrelor tablets are a P2Y 12 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 reduce the risk of stent thrombosis in patients who have been stented for treatment of ACS.
• 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).
• to reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale score ≤ 5) or high-risk transient ischemic attack (TIA). 1.1 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 reduce the risk of stent thrombosis in patients who have been stented for treatment of ACS [see Clinical Studies ] . 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 ] . 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 ] .

• 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.
• Patients with CAD and No Prior Stroke or MI o Administer 60 mg ticagrelor tablets twice daily.
• 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. Use ticagrelor tablets with a daily maintenance dose of aspirin of 75-100 mg. However, in patients who have undergone PCI, consider single antiplatelet therapy with ticagrelor tablets based on the evolving risk for thrombotic versus bleeding events. 2.1 General Instructions Advise patients who miss a dose of ticagrelor tablets 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 ] . Do not administer ticagrelor tablets with another oral P2Y 12 platelet inhibitor. Avoid aspirin at doses higher than recommended [see Clinical Studies ] . 2.2 Acute Coronary Syndrome or a History of Myocardial Infarction Initiate treatment with a 180 mg loading dose of ticagrelor tablets. Administer the first 90 mg maintenance dose of ticagrelor tablets, 6 to 12 hours after the loading dose. 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. Initiate ticagrelor tablets 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 tablets based on the evolving risk for thrombotic versus bleeding events [see Warnings and Precautions and Clinical Studies ] . 2.3 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction Administer 60 mg of ticagrelor tablets twice daily. Generally, use ticagrelor tablets with a daily maintenance dose of aspirin of 75 mg to 100 mg [see Clinical Studies ] . 2.4 Acute Ischemic Stroke or Transient Ischemic Attack (TIA) Initiate treatment with a 180 mg loading dose of ticagrelor tablets 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 tablets 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 Clinical Studies ] .

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.

The following adverse reactions are also discussed elsewhere in the labeling:

• Bleeding [see Warnings and Precautions ]
• Dyspnea [see Warnings and Precautions ] Most common adverse reactions (˃ 5%) are bleeding and dyspnea. To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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) PLATO Minor bleed: requires medical intervention to stop or treat bleeding. PLATO Major bleed: any one of the following: fatal; intracranial; intrapericardial with cardiac tamponade; hypovolemic shock or severe hypotension requiring intervention; significantly disabling (e.g., intraocular with permanent vision loss); associated with a decrease in Hb of at least 3 g/dL (or a fall in hematocrit (Hct) of at least 9%); transfusion of 2 or more units. PLATO Major bleed, fatal/life-threatening: any major bleed as described above and associated with a decrease in Hb of more than 5 g/dL (or a fall in hematocrit (Hct) of at least 15%); transfusion of 4 or more units. Fatal: A bleeding event that directly led to death within 7 days. Ticagrelor Tablets 90 mg BID N = 9235 Clopidogrel N = 9186 n (%) patients with event n (%) patients with event PLATO Major + Minor 713 567 Major 362 306 Fatal/Life-threatening 171 151 Fatal 15 16 Intracranial hemorrhage (Fatal/Life-threatening) 26 15 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 hemostatic 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) PLATO Major bleed: any one of the following: fatal; intracranial; intrapericardial with cardiac tamponade; hypovolemic shock or severe hypotension requiring intervention; significantly disabling (e.g., intraocular with permanent vision loss); associated with a decrease in Hb of at least 3 g/dL (or a fall in hematocrit (Hct) of at least 9%); transfusion of 2 or more units. PLATO Major bleed, fatal/life-threatening: any major bleed as described above and associated with a decrease in Hb of more than 5 g/dL (or a fall in hematocrit (Hct) of at least 15%); transfusion of 4 or more units. Ticagrelor Tablets 90 mg BID N = 770 Clopidogrel N = 814 n (%) patients with event n (%) patients with event PLATO Total Major 626 666 Fatal/Life-threatening 337 350 Fatal 6 7 When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of ticagrelor tablets treated patients and 79% on clopidogrel. Figure 1: Kaplan-Meier Estimate of Time to First Non-CABG PLATO-Defined Major Bleeding Event (PLATO) Figure 2: ‘Major Fatal/Life-Threatening’ CABG-Related Bleeding by Days from Last Dose of Study Drug to CABG Procedure (PLATO) 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 90 mg BID N = 9235 Clopidogrel N = 9186 Dyspnea 13.8

Dizziness 4.5

Nausea 4.3

3.8 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) TIMI Major: Fatal bleeding, OR any intracranial bleeding, OR clinically overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥ 5 g/dL, or a fall in hematocrit (Hct) of ≥ 15%. Fatal: A bleeding event that directly led to death within 7 days. TIMI Minor: Clinically apparent with 3-5 g/dL decrease in hemoglobin. Ticagrelor Tablets 60 mg BID 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 The bleeding profile of ticagrelor tablets 60 mg compared to aspirin alone was consistent across multiple pre-defined subgroups (e.g., 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 60 mg BID N = 6958 Placebo N = 6996 Dyspnea 14.2% 5.5% Dizziness 4.5% 4.1% Diarrhea 3.3% 2.5% 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) The bleeding events in THEMIS are shown below in Table 6. Table 6: Bleeding events (THEMIS) Ticagrelor Tablets N = 9562 Placebo N = 9531 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 Figure 3: Time to first TIMI Major bleeding event (THEMIS) Bleeding in THALES (Reduction in risk of stroke in patients with acute ischemic stroke or TIA) The Kaplan-Meier curve of time course of GUSTO severe bleeding events is presented in Figure 4. 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 : Any one of the following: fatal bleeding, intracranial bleeding (excluding asymptomatic hemorrhagic transformations of ischemic brain infarctions and excluding microhemorrhages 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. 6.2 Postmarketing Experience 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: Thrombotic Thrombocytopenic Purpura (TTP) has been rarely reported with the use of ticagrelor tablets. TTP is a serious condition which can occur after a brief exposure (< 2 weeks) and requires prompt treatment. Immune system disorders: Hypersensitivity reactions including angioedema [see Contraindications ]. Respiratory disorders: Central sleep apnea, Cheyne-Stokes respiration Skin and subcutaneous tissue disorders: Rash

• Avoid use with strong CYP3A inhibitors or CYP3A inducers.
• Opioids: Decreased exposure to ticagrelor. Consider use of parenteral anti-platelet agent.
• Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse effects.
• Rosuvastatin plasma concentrations may increase. Monitor for statin-related adverse effects.
• Monitor digoxin levels with initiation of or any change in ticagrelor tablets. 7.1 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 Clinical Pharmacology ]. 7.2 Strong CYP3A Inducers 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 Clinical Pharmacology ]. 7.3 Opioids As with other oral P2Y 12 inhibitors, co-administration of opioid agonists delay and reduce the absorption of ticagrelor and its active metabolite presumably because of slowed gastric emptying [see Clinical Pharmacology ] . Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists. 7.4 Simvastatin, Lovastatin, Rosuvastatin 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 ]. Ticagrelor tablets increase serum concentration of rosuvastatin because rosuvastatin is a BCRP substrate [see Clinical Pharmacology ] . 7.5 Digoxin Ticagrelor tablets inhibit the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in ticagrelor tablets therapy [see Clinical Pharmacology ].

• Lactation: Breastfeeding not recommended. 8.1 Pregnancy Risk Summary Available data from case reports with ticagrelor tablets 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 (MRHD) 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 MRHD (see Data ) . 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, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. 20 mg/kg/day is approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m 2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m 2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. At the mid-dose of 100 mg/kg/day (5.5 times the MRHD on a mg/m 2 basis), delayed development of liver and skeleton was seen. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m 2 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 mg/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 MRHD on a mg/m 2 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 MRHD on a mg/m 2 basis). 8.2 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 ticagrelor tablets. 8.4 Pediatric Use 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. 8.5 Geriatric Use 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. 8.6 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 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 and Clinical Pharmacology ]. 8.7 Renal Impairment No dosage adjustment is needed in patients with renal impairment [see Clinical Pharmacology ]. Patients with End-Stage Renal Disease on dialysis Clinical efficacy and safety studies with ticagrelor tablets 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 Clinical Pharmacology ] . It is not known whether these concentrations will lead to similar efficacy and safety in patients with ESRD on dialysis as were seen in PLATO, PEGASUS, THEMIS and THALES.