Brilique 60 mg film-coated tablets

Brilique 90 mg film-coated tablets

Brilique 60 mg film-coated tablets

Each film-coated tablet contains 60 mg ticagrelor.

Brilique 90 mg film-coated tablets

Each film-coated tablet contains 90 mg ticagrelor.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Brilique 60 mg film-coated tablets

Round, biconvex, pink tablets marked with '60' above 'T' on one side and plain on the other.

Brilique 90 mg film-coated tablets

Round, biconvex, yellow tablets marked with '90' above 'T' on one side and plain on the other.

Brilique, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with

- acute coronary syndromes (ACS) or

- a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event (see sections 4.2 and 5.1).

Posology

Patients taking Brilique should also take a daily low maintenance dose of ASA 75-150 mg, unless specifically contraindicated.

Acute coronary syndromes

Brilique treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily.

Treatment with Brilique 90 mg is recommended for 12 months in ACS patients unless discontinuation is clinically indicated (see section 5.1).

History of myocardial infarction

Brilique 60 mg twice daily is the recommended dose when an extended treatment is required for patients with a history of MI of at least one year and a high risk of an atherothrombotic event (see section 5.1). Treatment may be started without interruption as continuation therapy after the initial one-year treatment with Brilique 90 mg or other adenosine diphosphate (ADP) receptor inhibitor therapy in ACS patients with a high risk of an atherothrombotic event. Treatment can also be initiated up to 2 years from the MI, or within one year after stopping previous ADP receptor inhibitor treatment. There are limited data on the efficacy and safety of Brilique beyond 3 years of extended treatment.

If a switch is needed, the first dose of Brilique should be administered 24 hours following the last dose of the other antiplatelet medication.

Missed dose

Lapses in therapy should also be avoided. A patient who misses a dose of Brilique should take only one tablet (their next dose) at its scheduled time.

Special populations

Elderly

No dose adjustment is required in elderly (see section 5.2).

Renal impairment

No dose adjustment is necessary for patients with renal impairment (see section 5.2). No information is available concerning treatment of patients on renal dialysis and therefore ticagrelor is not recommended in these patients.

Hepatic impairment

Ticagrelor has not been studied in patients with severe hepatic impairment and its use in these patients is therefore contraindicated (see section 4.3). Only limited information is available in patients with moderate hepatic imparirment. Dose adjustment is not recommended, but ticagrelor should be used with caution (see sections 4.4 and 5.2). No dose adjustment is necessary for patients with mild hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of ticagrelor in children below the age of 18 years have not been established. No data are available.

Method of administration

For oral use.

Brilique can be administered with or without food.

For patients who are unable to swallow the tablet(s) whole, the tablets can be crushed to a fine powder and mixed in half a glass of water and drunk immediately. The glass should be rinsed with a further half glass of water and the contents drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater). It is important to flush the nasogastric tube through with water after administration of the mixture.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.8).

• Active pathological bleeding.

• History of intracranial haemorrhage (see section 4.8).

• Severe hepatic impairment (see section 4.2, 4.4 and 5.2).

• Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir) is contraindicated, as co-administration may lead to a substantial increase in exposure to ticagrelor (see section 4.5).

Bleeding risk

The use of ticagrelor in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events (see sections 4.8 and 5.1). If clinically indicated, ticagrelor should be used with caution in the following patient groups:

• Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery, coagulation disorders, active or recent gastrointestinal bleeding). The use of ticagrelor is contraindicated in patients with active pathological bleeding, in those with a history of intracranial haemorrhage, and in patients with severe hepatic impairment (see section 4.3).

• Patients with concomitant administration of medicinal products that may increase the risk of bleeding (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor dosing.

Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding. Since co-administration of ticagrelor with desmopressin did not decrease template-bleeding time, desmopressin is unlikely to be effective in managing clinical bleeding events (see section 4.5).

Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa therapy may increase haemostasis. Ticagrelor may be resumed after the cause of bleeding has been identified and controlled.

Surgery

Patients should be advised to inform physicians and dentists that they are taking ticagrelor before any surgery is scheduled and before any new medicinal product is taken.

In PLATO patients undergoing coronary artery bypass grafting (CABG), ticagrelor had more bleeding than clopidogrel when stopped within 1 day prior to surgery but a similar rate of major bleeds compared to clopidogrel after stopping therapy 2 or more days before surgery (see section 4.8). If a patient is to undergo elective surgery and antiplatelet effect is not desired, ticagrelor should be discontinued 7 days prior to surgery (see section 5.1).

Patients with prior ischaemic stroke

ACS patients with prior ischaemic stroke can be treated with Brilique for up to 12 months (PLATO study).

In PEGASUS, patients with history of MI with prior ischaemic stroke were not included. Therefore, in the absence of data, treatment beyond one year is not recommended in these patients.

Hepatic impairment

Use of ticagrelor is contraindicated in patients with severe hepatic impairment (see sections 4.2 and 4.3). There is limited experience with ticagrelor in patients with moderate hepatic impairment, therefore, caution is advised in these patients (see sections 4.2 and 5.2).

Patients at risk for bradycardic events

Due to observations of mostly asymptomatic ventricular pauses in an earlier clinical study, patients with an increased risk of bradycardic events (e.g. patients without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree AV block or bradycardic-related syncope) were excluded from the main studies eva luating the safety and efficacy of ticagrelor. Therefore, due to the limited clinical experience, ticagrelor should be used with caution in these patients (see section 5.1).

In addition, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia. However, no evidence of clinically significant adverse reactions was observed in the PLATO trial after concomitant administration with one or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin) (see section 4.5).

During the Holter substudy in PLATO, more patients had ventricular pauses ≥3 seconds with ticagrelor than with clopidogrel during the acute phase of their ACS. The increase in Holter-detected ventricular pauses with ticagrelor was higher in patients with chronic heart failure (CHF) than in the overall study population during the acute phase of ACS, but not at one month with ticagrelor or compared to clopidogrel. There were no adverse clinical consequences associated with this imalance (including syncope or pacemaker insertion) in this patient population (see section 5.1).

Dyspnoea

Dyspnoea was reported in patients treated with ticagrelor. Dyspnoea is usually mild to moderate in intensity and often resolves without need for treatment discontinuation. Patients with asthma/chronic obstructive pulmonary disease (COPD) may have an increased absolute risk of experiencing dyspnoea with ticagrelor. Ticagrelor should be used with caution in patients with history of asthma and/or COPD. The mechanism has not been elucidated. If a patient reports new, prolonged or worsened dyspnoea this should be investigated fully and if not tolerated, treatment with ticagrelor should be stopped. For further details see section 4.8.

Creatinine elevations

Creatinine levels may increase during treatment with ticagrelor. The mechanism has not been elucidated. Renal function should be checked according to routine medical practice. In patients with ACS, it is recommended that renal function is also checked one month after initiating the treatment with ticagrelor, paying special attention to patients ≥ 75 years, patients with moderate/severe renal impairment and those receiving concomitant treatment with an angiotensin receptor blocker (ARB).

Uric acid increase

Hyperuricaemia may occur during treatment with ticagrelor (see section 4.8). Caution is advised in patients with history of hyperuricaemia or gouty arthritis. As a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged.

Other

Based on a relationship observed in PLATO between maintenance ASA dose and relative efficacy of ticagrelor compared to clopidogrel, co-administration of ticagrelor and high maintenance dose ASA (>300 mg) is not recommended (see section 5.1).

Premature discontinuation

Premature discontinuation with any antiplatelet therapy, including Brilique, could result in an increased risk of cardiovascular (CV) death or MI due to the patient's underlying disease. Therefore, premature discontinuation of treatment should be avoided.

Ticagrelor is primarily a CYP3A4 substrate and a mild inhibitor of CYP3A4. Ticagrelor is also a P-glycoprotein (P-gp) substrate and a weak P-gp inhibitor and may increase the exposure of P-gp substrates.

Effects of other medicinal products on ticagrelor

Medicinal products metabolised by CYP3A4

CYP3A4 inhibitors

• Strong CYP3A4 inhibitors – Co-administration of ketoconazole with ticagrelor increased the ticagrelor C_max and AUC equal to 2.4-fold and 7.3-fold, respectively. The C_max and AUC of the active metabolite were reduced by 89% and 56%, respectively. Other strong inhibitors of CYP3A4 (clarithromycin, nefazodone, ritonavir, and atazanavir) would be expected to have similar effects and therefore concomitant use of strong CYP3A4 inhibitors with ticagrelor is contraindicated (see section 4.3).

• Moderate CYP3A4 inhibitors – Co-administration of diltiazem with ticagrelor increased the ticagrelor C_max by 69% and AUC to 2.7-fold and decreased the active metabolite C_max by 38% and AUC was unchanged. There was no effect of ticagrelor on diltiazem plasma levels. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, erythromycin and fluconazole) would be expected to have a similar effect and can as well be co-administered with ticagrelor.

CYP3A inducers

Co-administration of rifampicin with ticagrelor decreased ticagrelor C_max and AUC by 73% and 86%, respectively. The C_max of the active metabolite was unchanged and the AUC was decreased by 46%, respectively. Other CYP3A inducers (e.g. phenytoin, carbamazepine and phenobarbital) would be expected to decrease the exposure to ticagrelor as well. Co-administration of ticagrelor with potent CYP3A inducers may decrease exposure and efficacy of ticagrelor, therefore, their concomitant use with ticagrelor is discouraged.

Cyclosporine (P-gp and CYP3A inhibitor)

Co-administration of cyclosporine (600 mg) with ticagrelor increased ticagrelor C_max and AUC equal to 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite was increased by 32% and C_max was decreased by 15% in the presence of cyclosporine.

No data are available on concomitant use of ticagrelor with other active substances that also are potent P-gp inhibitors and moderate CYP3A4 inhibitors (e.g. verapamil, quinidine) that also may increase ticagrelor exposure. If the association cannot be avoided, their concomitant use should be made with caution.

Others

Clinical pharmacology interaction studies showed that co-administration of ticagrelor with heparin, enoxaparin and ASA or desmopressin did not have any effect on the pharmacokinetics of ticagrelor or the active metabolite or on ADP-induced platelet aggregation compared with ticagrelor alone. If clinically indicated, medicinal products that alter haemostasis should be used with caution in combination with ticagrelor.

A 2-fold increase of ticagrelor exposure was observed after daily consumption of large quantities of grapefruit juice (3x 200 ml). This magnitude of increased exposure is not expected to be clinically relevant to most patients.

Effects of ticagrelor on other medicinal products

Medicinal products metabolised by CYP3A4

• Simvastatin – Co-administration of ticagrelor with simvastatin increased simvastatin C_max by 81% and AUC by 56% and increased simvastatin acid C_max by 64% and AUC by 52% with some individual increases equal to 2 to 3-fold. Co-administration of ticagrelor with doses of simvastatin exceeding 40 mg daily could cause adverse effects of simvastatin and should be weighed against potential benefits. There was no effect of simvastatin on ticagrelor plasma levels. Ticagrelor may have similar effect on lovastatin. The concomitant use of ticagrelor with doses of simvastatin or lovastatin greater than 40 mg is not recommended.

• Atorvastatin - Co-administration of atorvastatin and ticagrelor increased atorvastatin acid C_max by 23% and AUC by 36%. Similar increases in AUC and C_max were observed for all atorvastatin acid metabolites. These increases are not considered clinically significant.

• A similar effect on other statins metabolised by CYP3A4 cannot be excluded. Patients in PLATO receiving ticagrelor took a variety of statins, with no concern of an association with statin safety among the 93% of the PLATO cohort taking these medicinal products.

Ticagrelor is a mild CYP3A4 inhibitor. Co-administration of ticagrelor and CYP3A4 substrates with narrow therapeutic indices (i.e. cisapride or ergot alkaloids) is not recommended, as ticagrelor may increase the exposure to these medicinal products.

P-gp substrates (including digoxin, cyclosporine)

Concomitant administration of ticagrelor increased the digoxin C_max by 75% and AUC by 28%. The mean trough digoxin levels were increased about 30% with ticagrelor co-administration with some individual maximum increases to 2 fold. In the presence of digoxin, the C_max and AUC of ticagrelor and its active metabolite were not affected. Therefore, appropriate clinical and/or laboratory monitoring is recommended when giving narrow therapeutic index P-gp dependent medicinal products like digoxin concomitantly with ticagrelor.

There was no effect of ticagrelor on cyclosporine blood levels. Effect of ticagrelor on other P-gp substrates has not been studied.

Medicinal products metabolised by CYP2C9

Co-administration of ticagrelor with tolbutamide resulted in no change in the plasma levels of either medicinal product, which suggests that ticagrelor is not a CYP2C9 inhibitor and unlikely to alter the CYP2C9 mediated metabolism of medicinal products like warfarin and tolbutamide.

Oral contraceptives

Co-administration of ticagrelor and levonorgestrel and ethinyl estradiol increased ethinyl estradiol exposure approximately 20% but did not alter the pharmacokinetics of levonorgestrel. No clinically relevant effect on oral contraceptive efficacy is expected when levonorgestrel and ethinyl estradiol are co-administered with ticagrelor.

Medicinal products known to induce bradycardia

Due to observations of mostly asymptomatic ventricular pauses and bradycardia, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia (see section 4.4). However, no evidence of clinically significant adverse reactions was observed in the PLATO trial after concomitant administration with one or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin).

Other concomitant therapy

In clinical studies, ticagrelor was commonly administered with ASA, proton pump inhibitors, statins, beta-blockers, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers as needed for concomitant conditions for long-term and also heparin, low molecular weight heparin and intravenous GpIIb/IIIa inhibitors for short durations (see section 5.1). No evidence of clinically significant adverse interactions with these medicinal products was observed.

Co-administration of ticagrelor with heparin, enoxaparin or desmopressin had no effect on activated partial thromboplastin time (aPTT), activated coagulation time (ACT) or factor Xa assays. However, due to potential pharmacodynamic interactions, caution should be exercised with the concomitant administration of ticagrelor with medicinal products known to alter haemostasis.

Due to reports of cutaneous bleeding abnormalities with SSRIs (e.g. paroxetine, sertraline and citalopram), caution is advised when administering SSRIs with ticagrelor as this may increase the risk of bleeding.

Women of childbearing potential

Women of childbearing potential should use appropriate contraceptive measures to avoid pregnancy during ticagrelor therapy.

Pregnancy

There are no or limited amount of data from the use of ticagrelor in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Ticagrelor is not recommended during pregnancy.

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of ticagrelor and its active metabolites in milk (see section 5.3). A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ticagrelor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Ticagrelor had no effect on male or female fertility in animals (see section 5.3).

Ticagrelor has no or negligible influence on the ability to drive and use machines. During treatment with ticagrelor, dizziness and confusion have been reported. Therefore, patients who experience these symptoms should be cautious while driving or using machines.