Cangrelor 50 mg Injection, Powder, Lyophilized, For Solution, 10 vials — NDC 68083-412-10 (Billing 68083-0412-10)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Cangrelor is a direct P2Y 12 platelet receptor inhibitor that blocks ADP-induced platelet activation and aggregation. Cangrelor binds selectively and reversibly to the P2Y 12 receptor to prevent further signaling and platelet activation.

12.2Pharmacodynamics Cangrelor inhibits activation and aggregation of platelets. After administration of a 30 mcg/kg IV bolus followed by a 4 mcg/kg/min IV infusion, platelet inhibition occurs within 2 minutes. Figure 2 shows the effect on platelet activity, and its relation to cangrelor plasma concentration, of administering a 30 mcg/kg IV bolus, followed by a 1-hour 4 mcg/kg/min IV infusion, of cangrelor.

The anti-platelet effect is maintained for the duration of the infusion. After discontinuation of the infusion, the anti-platelet effect decreases rapidly and platelet function returns to normal within 1 hour. cangrelor-spl-figure-2

12.3Pharmacokinetics Cangrelor administered intravenously has linear pharmacokinetics in both healthy volunteers and patients. Cangrelor is rapidly distributed and metabolized, reaching C max within 2 minutes after administration of an intravenous bolus followed by infusion. Distribution In a study in healthy volunteers, cangrelor administration at a dose of 30 mcg/kg bolus plus 4 mcg/kg/min showed a volume of distribution of

3.9L. Plasma protein binding of cangrelor is about 97 to 98%. Metabolism Cangrelor is deactivated rapidly in the circulation by dephosphorylation to its primary metabolite, a nucleoside, which has negligible anti-platelet activity.

Cangrelor's metabolism is independent of hepatic function and it does not interfere with other drugs metabolized by hepatic enzymes. Elimination Following IV administration of [ 3 H] cangrelor 58% of radioactivity was recovered in urine. The remaining 35% of radioactivity was in feces, presumably following biliary excretion.

The average elimination half-life of cangrelor is about 3 to 6 minutes. Specific Populations Cangrelor pharmacokinetics are not affected by sex, age, renal status or hepatic function. No dose adjustment is needed for these factors [see Use in Specific Populations (8) ].

Weight Although weight was a significant covariate for PK with higher clearance in heavier patients, the impact of weight on drug exposure is accounted by the use of weight-based dosing. Drug-Drug Interactions Co-administration of cangrelor with unfractionated heparin, aspirin, and nitroglycerin was formally studied in healthy subjects, with no evidence of an effect on the PK/PD of cangrelor. In clinical trials cangrelor has been co-administered with bivalirudin, low molecular weight heparin, clopidogrel, prasugrel, and ticagrelor without clinically detectable interactions.

The expected antiplatelet effect of a 600 mg loading dose of clopidogrel or a 60 mg loading dose of prasugrel was blocked when clopidogrel or prasugrel was administered during a cangrelor infusion [see Drug Interactions (7.1) ]. In contrast, the antiplatelet effect of a 180 mg ticagrelor loading dose was not altered significantly when ticagrelor was administered during cangrelor infusion [see Drug Interactions (7.1) ]. As shown in Figure 3, discontinuation of cangrelor infusion, followed by administration of the irreversible P2Y 12 platelet inhibitors clopidogrel and prasugrel led to a 1-hour decrease in IPA followed by an increase in inhibition of platelet aggregation beginning at about one hour.

This time course of platelet inhibition reflects the pharmacokinetics of cangrelor (offset) followed by the absorption and metabolism of clopidogrel and prasugrel to active metabolites (onset). Administration of ticagrelor, a reversible P2Y 12 platelet inhibitor, during the cangrelor infusion led to minimal decrease in platelet inhibition for approximately 0.5 hour following discontinuation of the cangrelor infusion. Administering ticagrelor during cangrelor infusion does not attenuate the anti-platelet effect o… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Cangrelor is a direct P2Y 12 platelet receptor inhibitor that blocks ADP-induced platelet activation and aggregation. Cangrelor binds selectively and reversibly to the P2Y 12 receptor to prevent further signaling and platelet activation.

12.3Pharmacokinetics Cangrelor administered intravenously has linear pharmacokinetics in both healthy volunteers and patients. Cangrelor is rapidly distributed and metabolized, reaching C max within 2 minutes after administration of an intravenous bolus followed by infusion. Distribution In a study in healthy volunteers, cangrelor administration at a dose of 30 mcg/kg bolus plus 4 mcg/kg/min showed a volume of distribution of

3.9L. Plasma protein binding of cangrelor is about 97 to 98%. Metabolism Cangrelor is deactivated rapidly in the circulation by dephosphorylation to its primary metabolite, a nucleoside, which has negligible anti-platelet activity.

Cangrelor's metabolism is independent of hepatic function and it does not interfere with other drugs metabolized by hepatic enzymes. Elimination Following IV administration of [ 3 H] cangrelor 58% of radioactivity was recovered in urine. The remaining 35% of radioactivity was in feces, presumably following biliary excretion.

The average elimination half-life of cangrelor is about 3 to 6 minutes. Specific Populations Cangrelor pharmacokinetics are not affected by sex, age, renal status or hepatic function. No dose adjustment is needed for these factors [see Use in Specific Populations (8) ].

Weight Although weight was a significant covariate for PK with higher clearance in heavier patients, the impact of weight on drug exposure is accounted by the use of weight-based dosing. Drug-Drug Interactions Co-administration of cangrelor with unfractionated heparin, aspirin, and nitroglycerin was formally studied in healthy subjects, with no evidence of an effect on the PK/PD of cangrelor. In clinical trials cangrelor has been co-administered with bivalirudin, low molecular weight heparin, clopidogrel, prasugrel, and ticagrelor without clinically detectable interactions.

The expected antiplatelet effect of a 600 mg loading dose of clopidogrel or a 60 mg loading dose of prasugrel was blocked when clopidogrel or prasugrel was administered during a cangrelor infusion [see Drug Interactions (7.1) ]. In contrast, the antiplatelet effect of a 180 mg ticagrelor loading dose was not altered significantly when ticagrelor was administered during cangrelor infusion [see Drug Interactions (7.1) ]. As shown in Figure 3, discontinuation of cangrelor infusion, followed by administration of the irreversible P2Y 12 platelet inhibitors clopidogrel and prasugrel led to a 1-hour decrease in IPA followed by an increase in inhibition of platelet aggregation beginning at about one hour.

This time course of platelet inhibition reflects the pharmacokinetics of cangrelor (offset) followed by the absorption and metabolism of clopidogrel and prasugrel to active metabolites (onset). Administration of ticagrelor, a reversible P2Y 12 platelet inhibitor, during the cangrelor infusion led to minimal decrease in platelet inhibition for approximately 0.5 hour following discontinuation of the cangrelor infusion. Administering ticagrelor during cangrelor infusion does not attenuate the anti-platelet effect of ticagrelor.

In vitro studies suggest that neither cangrelor nor its major metabolites inhibit the activity of the hepatic CYP isoenzymes at therapeutic concentrations. Therefore, cangrelor administration is not expected to interfere with the hepatic metabolism of other concomitantly administered therapeutic agents. cangrelor-spl-figure-3

12.2Pharmacodynamics Cangrelor inhibits activation and aggregation of platelets. After administration of a 30 mcg/kg IV bolus followed by a 4 mcg/kg/min IV infusion, platelet inhibition occurs within 2 minutes. Figure 2 shows the effect on platelet activity, and its relation to cangrelor plasma concentration, of administering a 30 mcg/kg IV bolus, followed by a 1-hour 4 mcg/kg/min IV infusion, of cangrelor.

The anti-platelet effect is maintained for the duration of the infusion. After discontinuation of the infusion, the anti-platelet effect decreases rapidly and platelet function returns to normal within 1 hour. cangrelor-spl-figure-2

14 CLINICAL STUDIES

14.1CHAMPION PHOENIX Trial The CHAMPION PHOENIX trial was intended to test whether faster platelet inhibition with cangrelor at the time of PCI would reduce the rate of periprocedural thrombotic events compared to a drug with a slower antiplatelet effect, clopidogrel, given at about the time of PCI. It was a randomized, double-blind study in which patients with coronary artery disease (stable angina, UA/NSTEMI, STEMI) requiring PCI and receiving standard therapy including aspirin and heparin or bivalirudin were randomized 1:1 to cangrelor (n=5472) or to clopidogrel 300 or 600 mg (n=5470).

Patients who had already taken an oral P2Y 12 platelet inhibitor were not eligible to enroll. Patients administered glycoprotein IIb/IIIa inhibitors (GPI) or for whom GPI use was planned were also not eligible to enroll. PHOENIX was thus a study of people undergoing PCI who had not been previously treated with anti-platelet therapy other than aspirin.

The primary outcome measure was the first occurrence of any one of the composite endpoint of all-cause mortality, myocardial infarction (MI), ischemia-driven revascularization (IDR), and stent thrombosis (ST) within 48 hours after randomization. Cangrelor was administered as 30 mcg/kg bolus followed by 4 mcg/kg/min infusion for 2 to 4 hours. Clopidogrel 600 mg was administered immediately at the end of the cangrelor infusion in patients randomized to cangrelor.

Clopidogrel 300 mg or 600 mg was administered shortly before PCI or shortly afterward, in patients randomized to clopidogrel. Cangrelor significantly reduced the occurrence of primary composite endpoint events compared to clopidogrel (relative risk reduction [RRR] 22%). Most of the effect was a reduction in post-procedural MIs detected solely by elevations in CK-MB (type 4a MI).

Cangrelor did not reduce the risk of death. Table 2 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. Table 2: Primary Endpoint and Its Component Events at 48 Hours in CHAMPION PHOENIX (mITT population a ) Cangrelor (N=5470) n (%) Clopidogrel (N=5469) n (%) Cangrelor vs.

Clopidogrel OR (95% CI) p-value Primary Endpoint Death/MI/IDR/ST 257 (4.7) 322 (5.9) 0.78 (0.66,0.93) b 0.005 Death 18 (0.3) 18 (0.3) MI 202 (3.7) 254 (4.6) IDR 10 (0.2) 14 (0.3) ST 27 (0.5) 36 (0.7) Note: if a subject had more than one event at 48 hours, then worst outcome counted (death >MI >IDR >ST) a The mITT population is all randomized subjects who received at least one dose of study drug and underwent the index PCI procedure b Based on logistic model adjusted for loading dose and baseline patient status for primary endpoint A supplementary analysis was also performed omitting two subcomponent events of the primary endpoint that were of lesser clinical significance: intraprocedural stent thrombosis (defined as a new or increasing thrombus within or adjacent to a deployed stent occurring during the index PCI procedure), and myocardial infarction with less than a 10-fold increase in CK-MB, or with less than a 5-fold increase in CK-MB in the presence of new Q waves or new left bundle branch block (LBBB).

These results are shown in Table 3. Table 3: Supplementary Endpoint and Its Component Events at 48 Hours in CHAMPION PHOENIX (mITT population) n (%) Cangrelor (N=5470) Clopidogrel (N=5469) Cangrelor vs. clopidogrel OR (95% CI) Supplementary Endpoint Death/SCAI-MI/IDR/ARC-ST 79 (1.4) 114 (2.1) 0.69 (0.52,0.92) Death 18 (0.3) 18 (0.3) SCAI-MI a 48 (0.9) 80 (1.5) IDR 13 (0.2) 16 (0.3) ARC-ST b 0 (0.0) 0 (0.0) Note: if a subject had more than one event at 48 hours, then worst outcome counted (death >SCAI-MI >IDR >ARC-ST) a SCAI MI: CK-MB ≥10X ULN, or CK-MB ≥5X ULN with new Q waves or new LBBB b ARC-ST defined according to the ARC definition [Cutlip et al.

2007] The effect of cangrelor appeared to be consistent in a variety of pre-specified and other clinically important subgroups (see Figure 4). a The mITT… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies were conducted. Mutagenesis Cangrelor was non-mutagenic and non-clastogenic in genetic toxicology studies, including in vitro bacterial gene mutation assay, mouse lymphoma thymidine kinase assay, chromosome aberration assay in human peripheral lymphocytes, and in vivo bone marrow micronucleus assay in mice. Impairment of Fertility Cangrelor had no significant effect on male or female rats fertility treated by continuous infusion for 28 days, or on early embryonic development at steady state plasma concentration (Css) of approximately the same as that achieved in the PCI setting at the MRHD.