- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Brilique 60 mg film-coated tabletsEach film-coated tablet contains 60 mg ticagrelor.
Brilique 90 mg film-coated tabletsEach film-coated tablet contains 90 mg ticagrelor.For the full list of excipients, see section 6.1.
Brilique 60 mg film-coated tabletsRound, biconvex, pink tablets marked with '60' above 'T' on one side and plain on the other.
Brilique 90 mg film-coated tabletsRound, biconvex, yellow tablets marked with '90' above 'T' on one side and plain on the other.
PosologyPatients taking Brilique should also take a daily low maintenance dose of ASA 75-150 mg, unless specifically contraindicated.
Acute coronary syndromesBrilique 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 infarctionBrilique 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 doseLapses 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.
ElderlyNo dose adjustment is required in elderly (see section 5.2).
Renal impairmentNo 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 impairmentTicagrelor 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 populationThe safety and efficacy of ticagrelor in children below the age of 18 years have not been established. No data are available.
Method of administrationFor 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.
Bleeding riskThe 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.No data exist in patients with ticagrelor regarding a haemostatic benefit of platelet transfusions; circulating ticagrelor may inhibit transfused platelets. 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.
SurgeryPatients 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 ischemic strokeACS patients with prior ischemic stroke can be treated with Brilique for up to 12 months (PLATO study).In PEGASUS, patients with history of MI with prior ischemic stroke were not included. Therefore, in the absence of data, treatment beyond one year is not recommended in these patients.
Hepatic impairmentUse 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 eventsDue 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 evaluating 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 imbalance (including syncope or pacemaker insertion) in this patient population (see section 5.1).
DyspnoeaDyspnoea 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 elevationsCreatinine 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 increaseHyperuricaemia 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.
OtherBased 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 discontinuationPremature 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.
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 Cmax and AUC equal to 2.4-fold and 7.3-fold, respectively. The Cmax 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 Cmax by 69% and AUC to 2.7-fold and decreased the active metabolite Cmax 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 inducersCo-administration of rifampicin with ticagrelor decreased ticagrelor Cmax and AUC by 73% and 86%, respectively. The Cmax 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 Cmax and AUC equal to 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite was increased by 32% and Cmax 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.
OthersClinical 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 Cmax by 81% and AUC by 56% and increased simvastatin acid Cmax 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 Cmax by 23% and AUC by 36%. Similar increases in AUC and Cmax 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 Cmax 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 Cmax 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 CYP2C9Co-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 contraceptivesCo-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 bradycardiaDue 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 therapyIn 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 potentialWomen of childbearing potential should use appropriate contraceptive measures to avoid pregnancy during ticagrelor therapy.
PregnancyThere 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-feedingAvailable 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.
FertilityTicagrelor had no effect on male or female fertility in animals (see section 5.3).
Summary of the safety profileThe safety profile of ticagrelor has been evaluated in two large phase 3 outcome trials (PLATO and PEGASUS) including more than 39,000 patients (see section 5.1).In PLATO, patients on ticagrelor had a higher incidence of discontinuation due to adverse events than clopidogrel (7.4% vs. 5.4%). In PEGASUS, patients on ticagrelor had a higher incidence of discontinuation due to adverse events compared to ASA therapy alone (16.1% for ticagrelor 60 mg with ASA vs. 8.5% for ASA therapy alone). The most commonly reported adverse reactions in patients treated with ticagrelor were bleeding and dyspnoea (see section 4.4).
Tabulated list of adverse reactionsThe following adverse reactions have been identified following studies or have been reported in post-marketing experience with ticagrelor (Table 1).Adverse reactions are listed by MedDRA and System Organ Class (SOC). Within each SOC the adverse reactions are ranked by frequency category. Frequency categories are defined according to the following conventions: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Table 1 Adverse reactions by frequency and system organ class (SOC)
|System Organ Classification||Very Common||Common||Uncommon|
|Neoplasms benign, malignant and unspecified (including cysts and polyps)||Tumour bleedingsa|
|Blood and lymphatic system disorders||Blood disorder bleedingsb|
|Immune system disorders||Hypersensitivity including angioedemac|
|Metabolism and nutrition disorders||Hyperuricaemiad||Gout/Gouty Arthritis|
|Nervous system disorders||Dizziness, Syncope, Headache||Intracranial haemorrhage|
|Eye disorders||Eye haemorrhagee|
|Ear and labyrinth disorders||Vertigo||Ear haemorrhage|
|Respiratory, thoracic and mediastinal disorders||Dyspnoea||Respiratory system bleedingsf|
|Gastrointestinal disorders||Gastrointestinal haemorrhageg, Diarrhoea, Nausea, Dyspepsia, Constipation||Retroperitoneal haemorrhage|
|Skin and subcutaneous tissue disorders||Subcutaneous or dermal bleedingh, Rash, Pruritus|
|Musculoskeletal connective tissue and bone||Muscular bleedingsi|
|Renal and urinary disorders||Urinary tract bleedingj|
|Reproductive system and breast disorders||Reproductive system bleedingsk|
|Investigations||Blood creatinine increasedd|
|Injury, poisoning and procedural complications||Post procedural haemorrhage, Traumatic bleedingsl|
Description of selected adverse reactions
Bleeding findings in PLATOOverall outcome of bleeding rates in the PLATO study are shown in Table 2.
Table 2 Analysis of overall bleeding events, Kaplan-Meier estimates at 12 months (PLATO)
|Ticagrelor 90 mg twice dailyN=9235||ClopidogrelN=9186||p-value*|
|PLATO Total Major||11.6||11.2||0.4336|
|PLATO Major Fatal/Life-Threatening||5.8||5.8||0.6988|
|Non-CABG PLATO Major||4.5||3.8||0.0264|
|Non-Procedural PLATO Major||3.1||2.3||0.0058|
|PLATO Total Major + Minor||16.1||14.6||0.0084|
|Non-Procedural PLATO Major + Minor||5.9||4.3||<0.0001|
|TIMI-defined Major + Minor||11.4||10.9||0.3272|
Bleeding findings in PEGASUSOverall outcome of bleeding events in the PEGASUS study are shown in Table 3.Table 3 Analysis of overall bleeding events, Kaplan-Meier estimates at 36 months (PEGASUS)
|Ticagrelor 60 mg twice daily + ASAN=6958||ASA aloneN=6996|
|Safety Endpoints||KM%||Hazard Ratio(95% CI)||KM%||p-value|
|TIMI-defined bleeding categories|
|TIMI Major||2.3||2.32 (1.68, 3.21)||1.1||<0.0001|
|Fatal||0.3||1.00 (0.44, 2.27)||0.3||1.0000|
|ICH||0.6||1.33 (0.77, 2.31)||0.5||0.3130|
|Other TIMI Major||1.6||3.61 (2.31, 5.65)||0.5||<0.0001|
|TIMI Major or Minor||3.4||2.54 (1.93, 3.35)||1.4||<0.0001|
|TIMI Major or Minor or Requiring medical attention||16.6||2.64 (2.35, 2.97)||7.0||<0.0001|
|PLATO-defined bleeding categories|
|PLATO Major||3.5||2.57 (1.95, 3.37)||1.4||<0.0001|
|Fatal/Life-threatening||2.4||2.38 (1.73, 3.26)||1.1||<0.0001|
|Other PLATO Major||1.1||3.37 (1.95, 5.83)||0.3||<0.0001|
|PLATO Major or Minor||15.2||2.71 (2.40, 3.08)||6.2||<0.0001|
DyspnoeaDyspnoea, a sensation of breathlessness, is reported by patients treated with Brilique. In PLATO, dyspnoea adverse events (AEs) (dyspnoea, dyspnoea at rest, dyspnoea exertional, dyspnoea paroxysmal nocturnal and nocturnal dyspnoea), when combined, was reported by 13.8% of patients treated with ticagrelor and by 7.8% of patients treated with clopidogrel. In 2.2% of patients taking ticagrelor and by 0.6% taking clopidogrel investigators considered the dyspnoea causally related to treatment in the PLATO study and few were serious (0.14% ticagrelor; 0.02% clopidogrel), (see section 4.4). Most reported symptoms of dyspnoea were mild to moderate in intensity, and most were reported as a single episode early after starting treatment. Compared with clopidogrel, patients with asthma/COPD treated with ticagrelor may have an increased risk of experiencing non-serious dyspnoea (3.29% ticagrelor versus 0.53% clopidogrel) and serious dyspnoea (0.38% ticagrelor versus 0.00% clopidogrel). In absolute terms, this risk was higher than in the overall PLATO population. Ticagrelor should be used with caution in patients with history of asthma and/or COPD (see section 4.4).About 30% of episodes resolved within 7 days. PLATO included patients with baseline congestive heart failure, COPD, or asthma; these patients, and the elderly, were more likely to report dyspnoea. For Brilique, 0.9% of patients discontinued study active substance because of dyspnoea compared with 0.1% taking clopidogrel. The higher incidence of dyspnoea with Brilique is not associated with new or worsening heart or lung disease (see section 4.4). Brilique does not affect tests of pulmonary function.In PEGASUS, dyspnoea was reported in 14.2% of patients taking ticagrelor 60 mg twice daily and in 5.5% of patients taking ASA alone. As in PLATO, most reported dyspnoea was mild to moderate in intensity (see section 4.4). Patients who reported dyspnoea tended to be older and more frequently had dyspnoea, COPD or asthma at baseline.
InvestigationsUric acid elevations: In PLATO, serum uric acid increased to more than upper limit of normal in 22% of patients receiving ticagrelor compared to 13% of patients receiving clopidogrel. The corresponding numbers in PEGASUS were 9.1%, 8.8% and 5.5% for ticagrelor 90 mg, 60 mg and placebo, respectively. Mean serum uric acid increased approximately 15% with ticagrelor compared to approximately 7.5% with clopidogrel and after treatment was stopped, decreased to approximately 7% on ticagrelor but with no decrease observed for clopidogrel. In PEGASUS, a reversible increase in mean serum uric acid levels of 6.3% and 5.6% was found for ticagrelor 90 mg and 60 mg, respectively, compared to a 1.5% decrease in the placebo group. In PLATO, the frequency of gouty arthritis was 0.2% for ticagrelor vs. 0.1% for clopidogrel. The corresponding numbers for gout/gouty arthritis in PEGASUS were 1.6%, 1.5% and 1.1% for ticagrelor 90 mg, 60 mg and placebo, respectively.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
UKYellow Card SchemeWebsite: www.mhra.gov.uk/yellowcard
IrelandHPRA PharmacovigilanceEarlsfort Terrace IRL - Dublin 2Tel: +353 1 6764971Fax: +353 1 6762517Website: www.hpra.iee-mail: email@example.com
MaltaADR ReportingWebsite: www.medicinesauthority.gov.mt/adrportal
Mechanism of actionBrilique contains ticagrelor, a member of the chemical class cyclopentyltriazolopyrimidines (CPTP), which is an oral, direct acting, selective and reversibly binding P2Y12 receptor antagonist that prevents ADP- mediated P2Y12 dependent platelet activation and aggregation. Ticagrelor does not prevent ADP binding but when bound to the P2Y12 receptor prevents ADP-induced signal transduction. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function has been shown to reduce the risk of CV events such as death, MI or stroke.Ticagrelor also increases local endogenous adenosine levels by inhibiting the equilibrative nucleoside transporter-1 (ENT-1). Ticagrelor has been documented to augment the following adenosine-induced effects in healthy subjects and in patients with ACS: vasodilation (measured by coronary blood flow increases in healthy volunteers and ACS patients; headache), inhibition of platelet function (in human whole blood in vitro) and dyspnoea. However, a link between the observed increases in adenosine and clinical outcomes (e.g. morbidity-mortality) has not been clearly elucidated.
Onset of actionIn patients with stable coronary artery disease (CAD) on ASA, ticagrelor demonstrates a rapid onset of pharmacological effect as demonstrated by a mean inhibition of platelet aggregation (IPA) for ticagrelor at 0.5 hours after 180 mg loading dose of about 41%, with the maximum IPA effect of 89% by 2-4 hours post dose, and maintained between 2-8 hours. 90% of patients had final extent IPA >70% by 2 hours post dose.
Offset of actionIf a CABG procedure is planned, ticagrelor bleeding risk is increased compared to clopidogrel when discontinued within less than 96 hours prior to procedure.
Switching dataSwitching from clopidogrel 75 mg to ticagrelor 90 mg twice daily results in an absolute IPA increase of 26.4% and switching from ticagrelor to clopidogrel results in an absolute IPA decrease of 24.5%. Patients can be switched from clopidogrel to ticagrelor without any interruption of antiplatelet effect (see section 4.2).
Clinical efficacy and safetyThe clinical evidence for the efficacy and safety of ticagrelor is derived from two phase 3 trials:• The PLATO [PLATelet Inhibition and Patient Outcomes] study, a comparison of ticagrelor to clopidogrel, both given in combination with ASA and other standard therapy.• The PEGASUS TIMI-54 [PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk AcUte Coronary Syndrome Patients] study, a comparison of ticagrelor combined with ASA to ASA therapy alone.
PLATO study (Acute Coronary Syndromes)The PLATO study included 18,624 patients who presented within 24 hours of onset of symptoms of unstable angina (UA), non ST elevation myocardial infarction (NSTEMI) or ST elevation myocardial infarction (STEMI), and were initially managed medically, or with percutaneous coronary intervention (PCI), or with CABG.
Clinical efficacyOn a background of daily ASA, ticagrelor 90 mg twice daily showed superiority to 75 mg daily clopidogrel in preventing the composite endpoint of CV death, MI, or stroke, with the difference driven by CV death and MI. Patients received a 300 mg loading dose of clopidogrel (600 mg possible if having PCI) or 180 mg of ticagrelor.The result appeared early (absolute risk reduction [ARR] 0.6% and relative risk reduction [RRR] of 12% at 30 days), with a constant treatment effect over the entire 12 month period, yielding ARR 1.9% per year with RRR of 16%. This suggests it is appropriate to treat patients with ticagrelor 90 mg twice daily for 12 months (see section 4.2). Treating 54 ACS patients with ticagrelor instead of clopidogrel will prevent 1 atherothrombotic event; treating 91 will prevent 1 CV death (see Figure 1 and Table 4).The treatment effect of ticagrelor over clopidogrel appears consistent across many subgroups, including weight; sex; medical history of diabetes mellitus, transient ischaemic attack or non-haemorrhagic stroke, or revascularisation; concomitant therapies including heparins, GpIIb/IIIa inhibitors and proton pump inhibitors (see section 4.5); final index event diagnosis (STEMI, NSTEMI, or UA); and treatment pathway intended at randomisation (invasive or medical).A weakly significant treatment interaction was observed with region whereby the hazard ratio (HR) for the primary endpoint favours ticagrelor in the rest of world but favours clopidogrel in North America, which represented approximately 10% of the overall population studied (interaction p-value=0.045). Exploratory analyses suggest a possible association with ASA dose such that reduced efficacy was observed with ticagrelor with increasing ASA doses. Chronic daily ASA doses to accompany Brilique should be 75-150 mg (see sections 4.2 and 4.4).Figure 1 shows the estimate of the risk to the first occurrence of any event in the composite efficacy endpoint.
Figure 1 Analysis of primary clinical composite endpoint of CV death, MI and stroke (PLATO)Ticagrelor reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI population (Table 4). Thus, Brilique 90 mg twice daily together with low-dose ASA can be used in patients with ACS (unstable angina, non ST elevation Myocardial Infarction [NSTEMI] or ST elevation Myocardial Infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG).
Table 4 - Analysis of primary and secondary efficacy endpoints (PLATO)
|Ticagrelor 90 mg twice daily(% patients with event)N=9333||Clopidogrel 75 mg once daily(% patients with event)N=9291||ARRa(%/yr)||RRRa (%) (95% CI)||p-value|
|CV death, MI (excl. silent MI) or stroke||9.3||10.9||1.9||16 ( 8, 23)||0.0003|
|Invasive intent||8.5||10.0||1.7||16 ( 6, 25)||0.0025|
|Medical intent||11.3||13.2||2.3||15 (0.3, 27)||0.0444d|
|CV death||3.8||4.8||1.1||21 ( 9, 31)||0.0013|
|MI (excl. silent MI)b||5.4||6.4||1.1||16 ( 5, 25)||0.0045|
|Stroke||1.3||1.1||-0.2||-17 (-52, 9)||0.2249|
|All-cause mortality, MI (excl. silent MI), or stroke||9.7||11.5||2.1||16 ( 8, 23)||0.0001|
|CV death, total MI, stroke, SRI, RI, TIA, or other ATEc||13.8||15.7||2.1||12 ( 5, 19)||0.0006|
|All-cause mortality||4.3||5.4||1.4||22 (11, 31)||0.0003d|
|Definite stent thrombosis||1.2||1.7||0.6||32 ( 8, 49)||0.0123d|
PLATO genetic substudyCYP2C19 and ABCB1 genotyping of 10,285 patients in PLATO provided associations of genotype groups with PLATO outcomes. The superiority of ticagrelor over clopidogrel in reducing major CV events was not significantly affected by patient CYP2C19 or ABCB1 genotype. Similar to the overall PLATO study, total PLATO Major bleeding did not differ between ticagrelor and clopidogrel, regardless of CYP2C19 or ABCB1 genotype. Non-CABG PLATO Major bleeding was increased with ticagrelor compared clopidogrel in patients with one or more CYP2C19 loss of function alleles, but similar to clopidogrel in patients with no loss of function allele.
Combined efficacy and safety compositeA combined efficacy and safety composite (CV death, MI, stroke, or PLATO-defined 'Total Major' bleeding) indicates that the benefit in efficacy of ticagrelor compared to clopidogrel is not offset by the major bleeding events (ARR 1.4%, RRR 8%, HR 0.92; p=0.0257) over 12 months after ACS.
Holter SubstudyTo study the occurrence of ventricular pauses and other arrhythmic episodes during PLATO, investigators performed Holter monitoring in a subset of nearly 3000 patients, of whom approximately 2000 had recordings both in the acute phase of their ACS and after one month. The primary variable of interest was the occurrence of ventricular pauses ≥3 seconds. More patients had ventricular pauses with ticagrelor (6.0%) than with clopidogrel (3.5%) in the acute phase; and 2.2% and 1.6% respectively after 1 month (see section 4.4). The increase in ventricular pauses in the acute phase of ACS was more pronounced in ticagrelor patients with history of CHF (9.2% versus 5.4% in patients without CHF history; for clopidogrel patients, 4.0% in those with versus 3.6% in those without CHF history) This imbalance did not occur at one month: 2.0% versus 2.1% for ticagrelor patients with and without CHF history respectively; and 3.8% versus 1.4% with clopidogrel. There were no adverse clinical consequences associated with this imbalance (including pacemaker insertions) in this population of patients.
PEGASUS study (History of Myocardial Infarction)The PEGASUS TIMI-54 study was a 21,162 patient, event-driven, randomised, double-blind, placebo-controlled, parallel group, international multicentre study to assess the prevention of atherothrombotic events with ticagrelor given at 2 doses (either 90 mg twice daily or 60 mg twice daily) combined with low dose ASA (75-150 mg), compared to ASA therapy alone in patients with history of MI and additional risk factors for atherothrombosis.Patients were eligible to participate if they were aged 50 years or over, with a history of MI (1 to 3 years prior to randomisation), and had at least one of the following risk factors for atherothrombosis: age ≥65 years, diabetes mellitus requiring medication, a second prior MI, evidence of multivessel CAD, or chronic non-end-stage renal dysfunction. Patients were ineligible if there was planned use of a P2Y12 receptor antagonist, dipyridamole, cilostazol, or anticoagulant therapy during the study period; if they had a bleeding disorder or a history of an ischemic stroke or intracranial bleeding, a central nervous system tumour, or an intracranial vascular abnormality; if they had had gastrointestinal bleeding within the previous 6 months or major surgery within the previous 30 days.
Clinical efficacyFigure 2 - Analysis of primary clinical composite endpoint of CV death, MI and stroke (PEGASUS)
Table 5 - Analysis of primary and secondary efficacy endpoints (PEGASUS)
|Ticagrelor 60 mg twice daily +ASA N = 7045||ASA alone N = 7067||p-value|
|Characteristic||Patients with events||KM %||HR (95% CI)||Patients with events||KM %|
|Composite of CV Death/MI /Stroke||487 (6.9%)||7.8%||0.84 (0.74, 0.95)||578 (8.2%)||9.0%||0.0043 (s)|
|CV death||174 (2.5%)||2.9%||0.83 (0.68, 1.01)||210 (3.0%)||3.4%||0.0676|
|MI||285 (4.0%)||4.5%||0.84 (0.72, 0.98)||338 (4.8%)||5.2%||0.0314|
|Stroke||91 (1.3%)||1.5%||0.75 (0.57, 0.98)||122 (1.7%)||1.9%||0.0337|
|CV death||174 (2.5%)||2.9%||0.83 (0.68, 1.01)||210 (3.0%)||3.4%||-|
|All-cause mortality||289 (4.1%)||4.7%||0.89 (0.76, 1.04)||326 (4.6%)||5.2%||-|
Clinical safetyThe rate of discontinuations with ticagrelor 60 mg due to bleeding and dyspnoea was higher in patients >75 years (42%) than in younger patients (range: 23-31%), with a difference versus placebo higher than 10% (42% vs. 29%) in patients >75 years.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with Brilique in all subsets of the paediatric population in the granted indication (see section 4.2 for information on paediatric use).
AbsorptionAbsorption of ticagrelor is rapid with a median tmax of approximately 1.5 hours. The formation of the major circulating metabolite AR-C124910XX (also active) from ticagrelor is rapid with a median tmax of approximately 2.5 hours. Following an oral ticagrelor 90 mg single dose under fasted conditions in healthy subjects, Cmax is 529 ng/ml and AUC is 3451 ng*h/ml. The metabolite parent ratios are 0.28 for Cmax and 0.42 for AUC. The pharmacokinetics of ticagrelor and AR-C124910XX in patients with a history of MI were generally similar to that in the ACS population. Based on a population pharmacokinetic analysis of the PEGASUS study the median ticagrelor Cmax was 391 ng/ml and AUC was 3801 ng*h/ml at steady state for ticagrelor 60 mg. For ticagrelor 90 mg Cmax was 627 ng/ml and AUC was 6255 ng*h/ml at steady state.The mean absolute bioavailability of ticagrelor was estimated to be 36%. Ingestion of a high-fat meal resulted in a 21% increase in ticagrelor AUC and 22% decrease in the active metabolite Cmax but had no effect on ticagrelor Cmax or the AUC of the active metabolite. These small changes are considered of minimal clinical significance; therefore, ticagrelor can be given with or without food. Ticagrelor as well as the active metabolite are P-gp substrates.Ticagrelor as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, has a comparable bioavailability to whole tablets with regards to AUC and Cmax for ticagrelor and the active metabolite. Initial exposure (0.5 and 1 hour post-dose) from crushed ticagrelor tablets mixed in water was higher compared to whole tablets, with a generally identical concentration profile thereafter (2 to 48 hours).
DistributionThe steady state volume of distribution of ticagrelor is 87.5 l. Ticagrelor and the active metabolite is extensively bound to human plasma protein (>99.0%).
BiotransformationCYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of the active metabolite and their interactions with other CYP3A substrates ranges from activation through to inhibition. The major metabolite of ticagrelor is AR-C124910XX, which is also active as assessed by in vitro binding to the platelet P2Y12 ADP-receptor. The systemic exposure to the active metabolite is approximately 30-40% of that obtained for ticagrelor.
EliminationThe primary route of ticagrelor elimination is via hepatic metabolism. When radiolabelled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in faeces, 26.5% 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 active metabolite is most likely via biliary secretion. The mean t1/2 was approximately 7 hours for ticagrelor and 8.5 hours for the active metabolite.
ElderlyHigher exposures to ticagrelor (approximately 25% for both Cmax and AUC) and the active metabolite were observed in elderly (≥75years) ACS patients compared to younger patients by the population pharmacokinetic analysis. These differences are not considered clinically significant (see section 4.2).
Paediatric populationTicagrelor has not been evaluated in a paediatric population (see sections 4.2 and 5.1).
GenderHigher exposures to ticagrelor and the active metabolite were observed in women compared to men. These differences are not considered clinically significant.
Renal impairmentExposure to ticagrelor was approximately 20% lower and exposure to the active metabolite was approximately 17% higher in patients with severe renal impairment (creatinine clearance <30 ml/min) compared to subjects with normal renal function (see section 4.2).
Hepatic impairmentCmax and AUC for ticagrelor were 12% and 23% higher in patients with mild hepatic impairment compared to matched healthy subjects, respectively, however, the IPA effect of ticagrelor was similar between the two groups. No dose adjustment is needed for patients with mild hepatic impairment. Ticagrelor has not been studied in patients with severe hepatic impairment and there is no pharmacokinetic information in patients with moderate hepatic impairment. In patients that had moderate or severe elevation in one or more liver function tests at baseline, ticagrelor plasma concentrations were on average similar or slightly higher as compared to those without baseline elevations. No dose adjustment is recommended in patients with moderate hepatic impairment (see sections 4.2 and 4.4).
EthnicityPatients of Asian descent have a 39% higher mean bioavailability compared to Caucasian patients. Patients self-identified as black had an 18% lower bioavailability of ticagrelor compared to Caucasian patients, in clinical pharmacology studies, the exposure (Cmax and AUC) to ticagrelor in Japanese subjects was approximately 40% (20% after adjusting for body weight) higher compared to that in Caucasians. The exposure in patients self-identified as Hispanic or Latino was similar to that in Caucasians.
Brilique 60 mg film-coated tablet
Tablet coreMannitol (E421)Calcium hydrogen phosphate dihydrateMagnesium stearate (E470b) Sodium starch glycolate type AHydroxypropylcellulose (E463)
Tablet coatingTitanium dioxide (E171)Iron oxide black (E172)Iron oxide red (E172)Macrogol 400Hypromellose (E464)
Brilique 90 mg film-coated tablet
Tablet coreMannitol (E421)Calcium hydrogen phosphate dihydrateMagnesium stearate (E470b)Sodium starch glycolate type AHydroxypropyl-cellulose (E463)
Tablet coatingTalcTitanium dioxide (E171)Iron oxide yellow (E172)Macrogol 400Hypromellose (E464)
Brilique 60 mg film-coated tablet• PVC-PVDC/Al transparent blister (with sun/moon symbols) of 10 tablets; cartons of 60 tablets (6 blisters) and 180 tablets (18 blisters).• PVC-PVDC/Al transparent calendar blister (with sun/moon symbols) of 14 tablets; cartons of 14 tablets (1 blister), 56 tablets (4 blisters), and 168 tablets (12 blisters).
Brilique 90 mg film-coated tablet• PVC-PVDC/Al transparent blister (with sun/moon symbols) of 10 tablets; cartons of 60 tablets (6 blisters) and 180 tablets (18 blisters).• PVC-PVDC/Al transparent calendar blister (with sun/moon symbols) of 14 tablets; cartons of 14 tablets (1 blister), 56 tablets (4 blisters), and 168 tablets (12 blisters).• PVC-PVDC/Al perforated unit dose transparent blister of 10 tablets; cartons of 100x1 tablets (10 blisters).Not all pack sizes may be marketed.
Brilique 60 mg film-coated tabletEU/1/10/655/007-011
Brilique 90 mg film-coated tabletEU/1/10/655/001-006
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