1.1 Acute Coronary Syndromes

BRILINTA is a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction). BRILINTA has been shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis [see Clinical Studies (14)].

BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily [see Warnings and Precautions (5.2) and Clinical Studies (14)].

4.1 History of Intracranial Hemorrhage

BRILINTA is 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)].

4.2 Active Bleeding

BRILINTA is 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 Severe Hepatic Impairment

BRILINTA is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure, and it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins [see Clinical Pharmacology (12.3)].

4.4 Hypersensitivity

BRILINTA is contraindicated in patients with hypersensitivity (e.g. angioedema) to ticagrelor or any component of the product [see Adverse Reactions (6.2)].

5.1 General Risk of Bleeding

Drugs that inhibit platelet function including BRILINTA increase the risk of bleeding. BRILINTA increased the overall risk of bleeding (Major + Minor) to a somewhat greater extent than did clopidogrel. The increase was seen for non-CABG-related bleeding, but not for CABG-related bleeding. Fatal and life-threatening bleeding rates were not increased [see Adverse Reactions (6.1)].

In general, risk factors for bleeding include older age, a history of bleeding disorders, performance of percutaneous invasive procedures, and concomitant use of medications that increase the risk of bleeding (e.g., anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal anti-inflammatory drugs [NSAIDS]).

When possible, discontinue BRILINTA five days prior to surgery. Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures, even if the patient does not have any signs of bleeding.

If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

5.2 Concomitant Aspirin Maintenance Dose

In PLATO, use of BRILINTA with maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Therefore, after the initial loading dose of aspirin (usually 325 mg), use BRILINTA with a maintenance dose of aspirin of 75-100 mg [see Dosage and Administration (2) and Clinical Studies (14)].

5.3 Moderate Hepatic Impairment

BRILINTA has not been studied in patients with moderate hepatic impairment. Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.

5.4 Dyspnea

In PLATO, dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment, but occasionally required discontinuation (0.9% of patients taking BRILINTA versus 0.1% of patients taking clopidogrel). If a patient develops new, prolonged, or worsened dyspnea during treatment with BRILINTA, exclude underlying diseases that may require treatment. If dyspnea is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption. In the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent.

In a substudy, 199 patients from PLATO underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no significant difference between treatment groups for FEV1. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment.

5.5 Discontinuation of BRILINTA

Avoid interruption of BRILINTA treatment. If BRILINTA must be temporarily discontinued (e.g., to treat bleeding or for elective surgery), restart it as soon as possible. Discontinuation of BRILINTA will increase the risk of myocardial infarction, stent thrombosis, and death.

5.6 Strong Inhibitors of Cytochrome CYP3A

Ticagrelor is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

5.7 Cytochrome CYP3A Potent Inducers

Avoid use with potent CYP3A inducers, such as rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

6.1 Clinical Trials Experience

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

 

Dyspnea [see Warnings and Precautions (5.4)]

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.

BRILINTA has been evaluated for safety in more than 10000 patients, including more than 3000 patients treated for more than 1 year.

Bleeding

PLATO used the following bleeding severity categorization:

•

Major bleed – fatal/life-threatening. Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells (PRBCs)) for bleeding.

•

Major bleed – other. Any one of the following: significantly disabling (e.g., intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2-3 units (whole blood or PRBCs) for bleeding.

•

Minor bleed. Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing).

•

Minimal bleed. All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or treatment.

Figure 1 shows major bleeding events over time. Many events are early, at a time of coronary angiography, PCI, CABG, and other procedures, but the risk persists during later use of antiplatelet therapy.

Figure 1- Kaplan-Meier estimate of time to first PLATO-defined ‘Total Major’ bleeding event

Annualized rates of bleeding are summarized in Table 1 below. About half of the bleeding events were in the first 30 days.

As shown in Table 1, BRILINTA was associated with a somewhat greater risk of non- CABG bleeding than was clopidogrel. No baseline demographic factor altered the relative risk of bleeding with BRILINTA compared to clopidogrel.

In PLATO, 1584 patients underwent CABG surgery. The percentages of those patients who bled are shown in Table 2. Rates were very high but similar for BRILINTA and clopidogrel.

Although the platelet inhibition effect of BRILINTA has a faster offset than clopidogrel in in vitro tests and BRILINTA is a reversibly binding P2Y12 inhibitor, PLATO did not show an advantage of BRILINTA compared to clopidogrel for CABG-related bleeding. When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of BRILINTA treated patients and 79% on clopidogrel.

No data exist with BRILINTA regarding a hemostatic benefit of platelet transfusions.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of BRILINTA. 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.

Immune system disorders – Hypersensitivity reactions including angioedema [see Contraindications (4.4)].

7.1 CYP3A inhibitors

Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

7.2 CYP3A inducers

Avoid use with potent inducers of CYP3A (e.g., rifampin, dexamethasone, phenytoin, carbamazepine and phenobarbital) [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)].

7.3 Aspirin

Use of BRILINTA with aspirin maintenance doses above 100 mg reduced the effectiveness of BRILINTA [see Warnings and Precautions (5.2) and Clinical Studies (14)].

Effect of BRILINTA on other drugs

Ticagrelor is an inhibitor of CYP3A4/5 and the P-glycoprotein transporter.

7.4 Simvastatin, lovastatin

BRILINTA will result in higher 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)].

7.5 Digoxin

Digoxin: Because of inhibition of the P-glycoprotein transporter, monitor digoxin levels with initiation of or any change in BRILINTA therapy [see Clinical Pharmacology (12.3)].

7.6 Other Concomitant Therapy

BRILINTA can be administered with unfractionated or low-molecular-weight heparin, GPIIb/IIIa inhibitors, proton pump inhibitors, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers.

8.1 Pregnancy

Pregnancy Category C:

There are no adequate and well-controlled studies of BRILINTA use in pregnant women. In animal studies, ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. BRILINTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. The lowest dose was 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. 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).

8.3 Nursing Mothers

It is not known whether ticagrelor or its active metabolites are excreted in human milk. Ticagrelor is excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from BRILINTA, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

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

8.5 Geriatric Use

In PLATO, 43% of patients were ≥65 years of age and 15% were ≥75 years of age. The relative risk of bleeding was similar in both treatment and age groups.

No overall differences in safety or effectiveness were observed between these patients and younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

BRILINTA has not been studied in the patients with moderate or severe hepatic impairment. Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Hence, BRILINTA is contraindicated for use in patients with severe hepatic impairment and its use should be considered carefully in patients with moderate hepatic impairment. No dosage adjustment is needed in patients with mild hepatic impairment [see Contraindications (4), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied [see Clinical Pharmacology (12.3)].

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 2, 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 3, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 3 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 2 - Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel

Figure 3 - 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 BRILINTA resulted in an absolute IPA increase of 26.4% and from BRILINTA to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to BRILINTA 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

Absorption of ticagrelor occurs with a median tmax of 1.5 h (range 1.0–4.0). The formation of the major circulating metabolite AR-C124910XX (active) from ticagrelor occurs with a median tmax of 2.5 h (range 1.5-5.0).

The mean absolute bioavailability of ticagrelor is about 36%, (range 30%-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. BRILINTA can be taken with or without food.

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 30-40% 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.

Special Populations

The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented in Figure 4. Effects are modest and do not require dose adjustment.

Figure 4 - Impact of intrinsic factors on the pharmacokinetics of ticagrelor

* BRILINTA has not been studied in patients with moderate or severe hepatic impairment.

Pediatric

Ticagrelor has not been evaluated in a pediatric population [see Use in Specific Populations (8.4)].

Body Weight

No dose adjustment is necessary for ticagrelor based on weight.

Smoking

Habitual smoking increased population mean clearance of ticagrelor by approximately 22% when compared to non-smokers. No dose adjustment is necessary for ticagrelor based on smoking status.

Effects of Other Drugs on BRILINTA

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 5 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.

Figure 5 - Effect of co-administered drugs on the pharmacokinetics of ticagrelor

* See Dosage and Administration (2).

Effects of BRILINTA 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, and digoxin, see Figure 6.

Figure 6 - Impact of BRILINTA on the pharmacokinetics of co-administered drugs

* Similar increases in AUC and Cmax were observed for all metabolites

** Monitor digoxin levels with initiation of or change in BRILINTA therapy

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).

17.1 Benefits and Risks

•

Tell patients to take BRILINTA exactly as prescribed.

•

Inform patients not to discontinue BRILINTA without discussing it with the prescribing physician.

•

Tell patients daily doses of aspirin should not exceed 100 mg and to avoid taking any other medications that contain aspirin.

•

Tell patients to read the Medication Guide.

17.2 Bleeding

Inform patients that they:

•

Will bleed and bruise more easily

•

Will take longer than usual to stop bleeding

•

Should report any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine.

17.3 Other Signs and Symptoms Requiring Medical Attention

•

Inform patients that BRILINTA can cause shortness of breath. Tell them to contact their doctor if they experience unexpected shortness of breath, especially if severe.

17.4 Invasive Procedures

Instruct patients to:

•

Inform physicians and dentists that they are taking BRILINTA before any surgery or dental procedure.

•

Tell the doctor performing any surgery or dental procedure to talk to the prescribing physician before stopping BRILINTA.

17.5 Concomitant Medications

Tell patients to list all prescription medications, over-the-counter medications or dietary supplements they are taking or plan to take so the physician knows about other treatments that may affect bleeding risk (e.g. warfarin, heparin).

Issued: 08/2013

BRILINTA® is a trademark of the AstraZeneca group of companies.

Distributed by: AstraZeneca LP, Wilmington, DE 19850

© AstraZeneca 2011, 2013