Drug Safety-related Labeling Changes (SrLC)

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BRILINTA (NDA-022433)

(TICAGRELOR)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/22/2024 (SUPPL-35)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Tell all of your healthcare providers and dentists that you are taking BRILINTA. They should talk to the healthcare provider who prescribed BRILINTA for you before you have any surgery or procedure.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. BRILINTA may affect the way other medicines work, and other medicines may affect how BRILINTA works. Certain medicines may increase your risk of bleeding.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take BRILINTA?

…

BRILINTA may also be given through certain nasogastric (NG) tubes. Ask your healthcare provider for instructions on how to take BRILINTA through a NG tube.

05/09/2022 (SUPPL-34)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and revisions underlined:

The safety and effectiveness of BRILINTA have not been established in pediatric patients. Effectiveness was not demonstrated in an adequate and well-controlled study conducted in 101 BRILINTA-treated pediatric patients, aged 2 to <18 for reducing the rate of vaso-occlusive crises in sickle cell disease.

08/10/2021 (SUPPL-32)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Central Sleep Apnea

(Newly added subsection)

Central sleep apnea (CSA) including Cheyne-Stokes respiration (CSR) has been reported in the post-marketing setting in patients taking ticagrelor, including recurrence or worsening of CSA/CSR following rechallenge. If central sleep apnea is suspected, consider further clinical assessment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

What are the possible side effects of BRILINTA? BRILINTA can cause serious side effects, including:

• See “What is the most important information I should know about BRILINTA?”

• Shortness of breath. Call your doctor if you have new or unexpected shortness of breath when you are at rest, at night, or when you are doing any activity. Your doctor can decide what treatment is needed.

• Irregular breathing. Tell your doctor if you develop irregular breathing patterns when asleep or awake such as speeding up, slowing down or short pauses in breathing. Your doctor will decide if you need further evaluation.

These are not all of the possible side effects of BRILINTA.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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11/05/2020 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Risk of Bleeding

(Section title revised)

(Additions and/or revisions underlined)

Drugs that inhibit platelet function including BRILINTA increase the risk of bleeding [see Adverse Reactions (6.1) and  Warnings and Precautions (5.4)].

Patients treated for acute ischemic stroke or TIA

Patients at NIHSS >5 and patients receiving thrombolysis were excluded from THALES and use of BRILINTA in such patients is not recommended.

5.2 Concomitant Aspirin Maintenance Dose for Patients Being Treated for ACS

(Section title revised)

(Additions and/or revisions underlined)

In the management of patients with ACS, the use of BRILINTA with maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. In such patients, use a maintenance dose of aspirin of 75-100 mg [see Dosage  and Administration (2.1) and Clinical Studies (14.1)].

5.3 Dyspnea

(Additions and/or revisions underlined)

In clinical trials, about 14% (PLATO and PEGASUS) to 21% (THEMIS) of patients treated with BRILINTA 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), 1.0% (THALES), 4.3% (PEGASUS), and 6.9% (THEMIS) of patients.

5.4 Discontinuation of BRILINTA in Patients Treated for Coronary Artery Disease

(Section title revised)

(Additions and/or revisions underlined)

Discontinuation of BRILINTA will increase the risk of myocardial infarction, stroke, and death in patients being treated for coronary artery disease. If BRILINTA must be temporarily discontinued (e.g., to treat bleeding or for significant surgery), restart it as soon as possible. When possible, interrupt therapy with BRILINTA for five days prior to surgery that has a major risk of bleeding. Resume BRILINTA as soon as hemostasis is achieved.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

About half of the patients in PLATO, PEGASUS, THEMIS, and THALES were > or equal to 65 years of age and at least 15% were > or equal to 75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients.

8.7 Renal Impairment

(Additions and/or revisions underlined)

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(Additions and/or revisions underlined)

In most cases, you should not take a dose of aspirin higher than 100 mg daily because it can affect how well BRILINTA works.

BRILINTA is a prescription medicine used to:

decrease your risk of stroke in people who are having a stroke (acute ischemic stroke) or mini-stroke (transient

ischemic attack or TIA).

• Take BRILINTA with aspirin as directed by your doctor.

09/15/2020 (SUPPL-30)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions underlined)

…

Respiratory Disorders: Central sleep apnea, Cheyne-Stokes respiration

05/28/2020 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.3 Dyspnea

In clinical trials, about 14% (PLATO and PEGASUS) to 21% (THEMIS) of patients treated with BRILINTA 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.

5.5 Bradyarrhythmias

BRILINTA 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

BRILINTA 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.

Following 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)

Table 6 – Bleeding events (THEMIS)

Bradycardia

In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with BRILINTA (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).

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

About half of the patients in PLATO, PEGASUS and THEMIS were greater than or equal to 65 years of age and about 15% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is BRILINTA?

BRILINTA is a prescription medicine used to:

• decrease your risk of death, heart attack, and stroke in people with a blockage of blood flow to the heart (acute coronary syndrome or ACS) or a history of a heart attack. BRILINTA can also decrease your risk of blood clots in your stent in people who have received stents for the treatment of ACS.

• decrease your risk of a first heart attack or stroke in people who have a condition where the blood flow to the heart is decreased (coronary artery disease or CAD) who are at high risk for having a heart attack or stroke.

It is not known if BRILINTA is safe and effective in children.

10/24/2019 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Laboratory Test Interferences

(newly added subsection)

False negative functional tests for Heparin Induced Thrombocytopenia (HIT)

BRILINTA 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 BRILINTA is required for interpretation of HIT functional tests. Based on the mechanism of BRILINTA interference, BRILINTA is not expected to impact PF4 antibody testing for HIT.

6 Adverse Reactions

6.2 Postmarketing Experience

(additions and/or revisions are underlined)

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.

Blood and lymphatic system disorders: Thrombotic Thrombocytopenic Purpura (TTP) has been rarely reported with the use of BRILINTA. 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

Skin and subcutaneous tissue disorders: Rash

04/03/2019 (SUPPL-23)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

 

Available data from case reports with BRILINTA 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

(PLLR conversion)

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 BRILINTA.

8.7 Renal Impairment

(additions underlined)

No dosage adjustment is needed in patients with renal impairment.

 

Patients with End-Stage Renal Disease on dialysis

 

Clinical efficacy and safety studies with BRILINTA 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. 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 and PEGASUS.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

 

(addition underlined)

…

 

Advise women that breastfeeding is not recommended during treatment with BRILINTA.

 

…

03/09/2018 (SUPPL-22)

Approved Drug Label (PDF)

7 Drug Interactions

Newly added subsection:

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. Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

09/23/2016 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Bradyarrhythmias (new section)

• Ticagrelor can cause ventricular pauses. 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 PLATO and PEGASUS and may be at increased risk of developing bradyarrhythmias with ticagrelor.

07/22/2016 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

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.

• Immune system disorders: Hypersensitivity reactions including angioedema
• Skin and subcutaneous tissue disorders: Rash