Ticagrelor 60 mg Tablet, Film Coated, 60-count — NDC 0480-2688-06 (Billing 00480-2688-06)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Ticagrelor and its major metabolite reversibly interact with the platelet P2Y 12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.

12.2Pharmacodynamics The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6-week study examining both acute and chronic platelet inhibition effects in response to 20 μM ADP as the platelet aggregation agonist. The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. As shown in Figure 5, IPA was higher in the ticagrelor group at all time points.

The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least 8 hours. The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP. As shown in Figure 6, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel.

The insert in Figure 6 shows that after 24 hours, IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%), indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk or thrombotic risk track with IPA, for either ticagrelor or clopidogrel.

Figure 5 - Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel Figure 6 - Mean inhibition of platelet aggregation (IPA) following 6 weeks on placebo, ticagrelor 90 mg twice daily, or clopidogrel 75 mg daily Transitioning from clopidogrel to ticagrelor resulted in an absolute IPA increase of 26.4% and from ticagrelor to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to ticagrelor without interruption of antiplatelet effect [see Dosage and Administration ( 2 )] . new5 new6

12.3Pharmacokinetics Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers. Absorption Ticagrelor can be taken with or without food. Absorption of ticagrelor occurs with a median t max 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 t max 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 C max , but resulted in a 21% increase in AUC.

The C max of its major metabolite was decreased by 22% with no change in AUC. Ticagrelor as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and C max within 80% to 125% for ticagrelor and AR­-C124910XX) with a median t max 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. Ticagrelor is a BCRP inhibitor. Excretion The primary route of ticagrelor elimination is hepatic metabolism.

When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Ticagrelor and its major metabolite reversibly interact with the platelet P2Y 12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.

12.3Pharmacokinetics Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers. Absorption Ticagrelor can be taken with or without food. Absorption of ticagrelor occurs with a median t max 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 t max 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 C max , but resulted in a 21% increase in AUC.

The C max of its major metabolite was decreased by 22% with no change in AUC. Ticagrelor as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and C max within 80% to 125% for ticagrelor and AR­-C124910XX) with a median t max 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. Ticagrelor is a BCRP inhibitor. Excretion The primary route of ticagrelor elimination is hepatic metabolism.

When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion.

The mean t 1/2 is approximately 7 hours for ticagrelor and 9 hours for the active metabolite. Specific Populations The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented in Figure 7. Effects are modest and do not require dose adjustment.

Patients with End-Stage Renal Disease on Hemodialysis In patients with end stage renal disease on hemodialysis AUC and C max of ticagrelor 90 mg administered on a day without dialysis were 38% and 51% higher respectively, compared to subjects with normal renal function. A similar increase in exposure was observed when ticagrelor was administered immediately prior to dialysis showing that ticagrelor is not dialyzable. Exposure of the active metabolite increased to a lesser extent.

The IPA effect of ticagrelor was independent of dialysis in patients with end stage renal disease and similar to healthy adults with normal renal function. Figure 7 - Impact of intrinsic factors on the pharmacokinetics of ticagrelor * Single dose of ticagrelor administered on a day without dialysis. ** Ticagrelor has not been studied in patients with moderate or severe hepatic impairment. Effects of Other Drugs on Ticagrelor CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite.

The effects of other drugs on the pharmacokinetics of ticagrelor are presented in Figure 8 as change relative to ticagrelor given alone (test/reference). Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) substantially increase ticagrelor exposure. Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem).

CYP3A inducers (e.g., rifampin) substantially reduce ticagrelor blood levels. P-gp inhibitors (e.g., cyclosporine) increase ticagrelor exposure. Coadministration 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 P… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6-week study examining both acute and chronic platelet inhibition effects in response to 20 μM ADP as the platelet aggregation agonist. The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. As shown in Figure 5, IPA was higher in the ticagrelor group at all time points.

The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least 8 hours. The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP. As shown in Figure 6, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel.

The insert in Figure 6 shows that after 24 hours, IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%), indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk or thrombotic risk track with IPA, for either ticagrelor or clopidogrel.

Figure 5 - Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel Figure 6 - Mean inhibition of platelet aggregation (IPA) following 6 weeks on placebo, ticagrelor 90 mg twice daily, or clopidogrel 75 mg daily Transitioning from clopidogrel to ticagrelor resulted in an absolute IPA increase of 26.4% and from ticagrelor to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to ticagrelor without interruption of antiplatelet effect [see Dosage and Administration ( 2 )] . new5 new6

14 CLINICAL STUDIES

14.1Acute 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) Ticagrelor* Clopidogrel Hazard Ratio p- value N=9,333 N=9,291 (95% CI) Events / 1,000 patient years Events / 1,000 patient years Composite of CV death, MI, or stroke 111 131 0.84 (0.77, 0.92) 0.0003 CV death 32 43

0.74 Non-fatal MI 64 76

0.84 Non-fatal stroke 15 12

1.24Secondary endpoints † CV death 45 57 0.79 (0.69, 0.91) 0.0013 MI ‡ 65 76 0.84 (0.75, 0.95) 0.0045 Stroke ‡ 16 14 1.17 (0.91, 1.52)

0.22All-cause mortality 51 65 0.78 (0.69, 0.89) 0.0003 * Dosed at 90 mg bid. † Note: rates of first events for the components CV Death, MI and Stroke are the actual rates for first events for each component and do not add up to the overall rate of events in the composite endpoint. ‡ Including patients who could have had other non-fatal events or died. 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 (1.9%) (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 tr… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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).