1.1  Acute Coronary Syndrome or a History of Myocardial Infarction

Ticagrelor tablets are indicated to reduce the risk of cardiovascular 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 (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 were established in a population with type 2 diabetes mellitus (T2DM).

2.1 Acute Coronary Syndrome or a History of Myocardial Infarction

In the management of ACS, initiate ticagrelor tablets 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.

2.2 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction

Administer 60 mg twice daily. For all patients with ACS [see Dosage and Administration (2.1)].

2.3   Administration

Administer ticagrelor tablets with a daily maintenance dose of aspirin of 75 mg to 100 mg [see Warnings and Precautions (5.2) and Clinical Studies (14)]. A patient who misses a dose of ticagrelor tablets should take one tablet (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 tablets with another oral P2Y12 platelet inhibitor.

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.

5.1 General Risk of Bleeding

Drugs that inhibit platelet function including ticagrelor increase the risk of bleeding [see Adverse Reactions (6.1)].

If possible, manage bleeding without discontinuing ticagrelor. Stopping ticagrelor increases the risk of subsequent cardiovascular events [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

5.2 Concomitant Aspirin Maintenance Dose

In PLATO the use of ticagrelor with maintenance doses of aspirin above 100 mg decreased the effectiveness of ticagrelor. Therefore, after the initial loading dose of aspirin, use ticagrelor with a maintenance dose of aspirin of 75 mg to 100 mg [see Dosage and Administration (2.3) and Clinical Studies (14.1)].

5.3 Dyspnea

In clinical trials, about 14% (PLATO and PEGASUS) to 21% (THEMIS) of patients treated with ticagrelor 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), 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, no specific treatment is required; continue ticagrelor without interruption if possible. In the case of intolerable dyspnea requiring discontinuation of ticagrelor, consider prescribing another antiplatelet agent.

5.4 Discontinuation of Ticagrelor

Discontinuation of ticagrelor will increase the risk of myocardial infarction, stroke, and death. If ticagrelor 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 for five days prior to surgery that has a major risk of bleeding. Resume ticagrelor as soon as hemostasis is achieved.

5.5 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, 2nd or 3rd 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.

5.6 Severe Hepatic Impairment

Avoid use of ticagrelor 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 Clinical Pharmacology (12.3)].

5.7 Laboratory Test Interferences

False negative functional tests for Heparin Induced Thrombocytopenia (HIT)

Ticagrelor has been reported to cause false negative results in platelet functional tests (to include, but may not be limited to, the heparin-induced platelet aggregation (HIPA) assay) for patients with Heparin Induced Thrombocytopenia (HIT). This is related to inhibition of the P2Y12-receptor on the healthy donor platelets in the test by ticagrelor in the affected patient’s serum/plasma. Information on concomitant treatment with ticagrelor is required for interpretation of HIT functional tests. Based on the mechanism of ticagrelor interference, ticagrelor is not expected to impact PF4 antibody testing for HIT.

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 has been evaluated for safety in more than 32,000 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)

No baseline demographic factor altered the relative risk of bleeding with ticagrelor compared to clopidogrel.

In PLATO, 1,584 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)

When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of ticagrelor 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 (PLATO)

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)

The bleeding profile of ticagrelor 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)

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)

Bradycardia

In a Holter substudy of about 3,000 patients in PLATO, more patients had ventricular pauses with ticagrelor (6.0%) than with clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6%, respectively, after 1 month. PLATO, PEGASUS and THEMIS excluded patients at increased risk of bradycardic events (e.g., 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 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 60 mg and no elevation was observed on aspirin alone. Gout occurred more commonly in patients on ticagrelor than in patients on aspirin alone (1.5%, 1.1%). 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 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 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. 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. 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 (4.3)].

Skin and subcutaneous tissue disorders: Rash

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 (12.3)].

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 (12.3)].

7.3 Aspirin

Use of ticagrelor with aspirin maintenance doses above 100 mg reduced the effectiveness of ticagrelor [see Warnings and Precautions (5.2) and Clinical Studies (14.1)].

7.4 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 [see Clinical Pharmacology (12.3)]. Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

7.5 Simvastatin, Lovastatin

Ticagrelor increases 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)].

7.6 Digoxin

Ticagrelor inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in ticagrelor therapy [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Risk Summary

Available data from case reports with ticagrelor 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/m2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m2 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/m2 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/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 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/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 MRHD on a mg/m2 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.

8.4 Pediatric Use

The safety and effectiveness of ticagrelor in pediatric patients have not been established.

8.5 Geriatric Use

About half of the patients in PLATO, PEGASUS and THEMIS 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.

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 in patients with severe hepatic impairment. There is limited experience with ticagrelor 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 (5.5) and Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dosage adjustment is needed in patients with renal impairment [see Clinical Pharmacology (12.3)].

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 Clinical Pharmacology (12.3)]. It is not 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, PEGASUS, and THEMIS.

12.1 Mechanism of Action

Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 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 4, 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 5, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 5 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 4: Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel

Figure 5: 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)].

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 to 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 to 5.0).

The mean absolute bioavailability of ticagrelor is about 36% (range 30% to 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.

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 Cmax within 80% to 125% for ticagrelor and AR-C124910XX) with a median tmax of 1.0 hour (range 1.0 to 4.0) for ticagrelor and 2.0 hours (range 1.0 to 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% to 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 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 6. 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 6: Impact of intrinsic factors on the pharmacokinetics of ticagrelor

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 7 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 to 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 7: Effect of co-administered drugs on the pharmacokinetics of ticagrelor

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, levonorgesterol, tolbutamide, digoxin and cyclosporine, see Figure 8.

Figure 8: Impact of ticagrelor on the pharmacokinetics of co-administered drugs

12.5 Pharmacogenetics

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.

13.1 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 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).

14.1 Acute Coronary Syndromes and Secondary Prevention after Myocardial Infarction

PLATO

PLATO (NCT00391872) was a randomized double-blind study comparing ticagrelor (N=9,333) to clopidogrel (N=9,291), both given in combination with aspirin and other standard therapy, in patients with acute coronary syndromes (ACS), who presented within 24 hours of onset of the most recent episode of chest pain or symptoms. The study’s primary endpoint was the composite of first occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke.

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 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 mg to 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 (PLATO)

The Kaplan-Meier curve (Figure 9) 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 9: 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 (1.9%) (HR 0.67, 95% CI 0.50 to 0.91; p=0.009). 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 10. 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.g., aspirin maintenance dose, use of PCI).

Figure 10: 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 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 11 shows results by region and dose.

Figure 11: 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.

PEGASUS

The PEGASUS TIMI-54 study (NCT01225562) was a 21,162-patient, randomized, double-blind, placebo-controlled, parallel-group study. Two doses of ticagrelor, either 90 mg twice daily or 60 mg twice daily, co-administered with 75 mg to 150 mg of aspirin, were compared to aspirin therapy alone in patients with history of MI. The primary endpoint was the composite of first occurrence of CV death, non-fatal MI and non-fatal stroke. CV death and all-cause mortality were assessed as secondary endpoints.

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. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. 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 65 years, and 99.8% of patients received prior aspirin therapy. See Table 8 for key baseline features.

Table 8: Baseline features (PEGASUS)

The Kaplan-Meier curve (Figure 12) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke.

Figure 12: Time to First Occurrence of CV death, MI or Stroke (PEGASUS)

Ti = Ticagrelor BID; CI = Confidence interval; HR = Hazard ratio; KM = Kaplan-Meier; N = Number of patients.

Both the 60 mg and 90 mg regimens of ticagrelor 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 plus aspirin vs. aspirin alone were 1.27% and 1.19% for the 60 mg 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 9 shows the results for the 60 mg plus aspirin regimen vs. aspirin alone.

Table 9: Incidences of the primary composite endpoint, primary composite endpoint components, and secondary endpoints (PEGASUS)

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.

The treatment effect of ticagrelor 60 mg over aspirin appeared similar across most pre-defined subgroups, see Figure 13.

Figure 13: 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. 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.

14.2 Coronary Artery Disease but No Prior Stroke or Myocardial Infarction

THEMIS

The THEMIS study (NCT01991795) was a double-blind, parallel group, study in which 19,220 patients with CAD and Type 2 Diabetes Mellitus (T2DM) but no history of MI or stroke were randomized to twice daily ticagrelor or placebo, on a background of 75 mg to 150 mg of aspirin. The primary endpoint was the composite of first occurrence of CV death, MI, and stroke. CV death, MI, ischemic stroke, and all-cause death were assessed as secondary endpoints.

Patients were eligible to participate if they were ≥ 50 years old with CAD, defined as a history of PCI or CABG, or angiographic evidence of ≥ 50% lumen stenosis of at least 1 coronary artery and T2DM treated for at least 6 months with glucose-lowering medication. Patients with previous intracerebral hemorrhage, gastrointestinal bleeding within the past 6 months, known bleeding diathesis, and coagulation disorder were excluded. Patients taking anticoagulants or ADP receptor antagonists were excluded from participating, and patients who developed an indication for those medications during the trial were discontinued from study drug.

Patients were treated for a median of 33 months and up to 58 months.

Patients were predominantly male (69%) with a mean age of 66 years. At baseline, 80% had a history of coronary artery revascularization; 58% had undergone PCI, 29% had undergone a CABG and 7% had undergone both. The proportion of patients studied in the US was 12%. Patients in THEMIS had established CAD and other risk factors that put them at higher cardiovascular risk; see Table 10.

Table 10: Baseline risk factors (THEMIS)

Ticagrelor was superior to placebo in reducing the incidence of CV death, MI, or stroke. The effect on the composite endpoint was driven by the individual components MI and stroke; see Table 11.

Table 11: Primary composite endpoint, primary endpoint components, and secondary endpoints (THEMIS)

Figure 14: Time to First Occurrence of CV death, MI or Stroke (THEMIS)

The treatment effect of ticagrelor appeared similar across patient subgroups, see Figure 15.

Figure 15: Subgroup analyses of ticagrelor (THEMIS)

Note: The figure above presents effects in various subgroups all of which are baseline characteristics. 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.