ticagrelor: prescribing information – dosing, contraindications, interactions, side effects

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 twice daily is recommended for 12 months in ACS patients unless discontinuation is clinically indicated (see section 5.1).

Discontinuation of ASA may be considered after 3 months in patients with ACS who have undergone a percutaneous coronary intervention (PCI) procedure and have an increased risk of bleeding. In that case, ticagrelor as single antiplatelet therapy should be continued for 9 months (see section 4.4).

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 ticagrelor 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).

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 impairment. 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.
There is no relevant use of ticagrelor in children with sickle cell disease (see sections 5.1 and 5.2).

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.

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 twice daily is recommended for 12 months in ACS patients unless discontinuation is clinically indicated (see section 5.1).

Discontinuation of ASA may be considered after 3 months in patients with ACS who have undergone a percutaneous coronary intervention (PCI) procedure and have an increased risk of bleeding. In that case, ticagrelor as single antiplatelet therapy should be continued for 9 months (see section 4.4).

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 ticagrelor 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).

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 impairment. 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.
There is no relevant use of ticagrelor in children with sickle cell disease (see sections 5.1 and 5.2).

Method of administration
For oral use.
Brilique can be administered with or without food.
The orodispersible tablets may be used as an alternative to Brilique 90 mg film-coated tablets for patients who have difficulty swallowing the tablets whole or for whom there is a preference for orodispersible tablets. The tablet should be placed on the tongue, where it will rapidly disperse in saliva. It can then be swallowed with or without water (see section 5.2). The tablet can also be dispersed in water and administered via a nasogastric tube (CH8 or greater). It is important to flush the nasogastric tube through with water after administration of the mixture. A 60 mg orodispersible tablet is not available.

• 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 sections 4.2, 4.4 and 5.2).
• Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir), as co-administration may lead to a substantial increase in exposure to ticagrelor (see section 4.5).

Summary of the safety profile
The 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 reactions
The 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 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)

SOC
Very common

Common

Uncommon

Not known
Neoplasms benign, malignant and unspecified
(including cysts and polyps)

Tumour bleedingsa

Blood and lymphatic system disorders
Blood disorder bleedingsb

Thrombotic
Thrombocytopenic
Purpurac
Immune system disorders

Hypersensitivity including angioedemac

SOC
Very common

Common

Uncommon

Not known
Metabolism and nutrition disorders
Hyperuricaemiad Gout/Gouty
Arthritis

Psychiatric disorders

Confusion

Nervous system disorders

Dizziness,
Syncope,
Headache
Intracranial haemorrhagem

Eye disorders

Eye haemorrhagee

Ear and labyrinth disorders

Vertigo
Ear haemorrhage

Cardiac disorders

Bradyarrhythmia,
AV blockc
Vascular disorders

Hypotension

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

a e.g. bleeding from bladder cancer, gastric cancer, colon cancer b e.g. increased tendency to bruise, spontaneous haematoma, haemorrhagic diathesis c Identified in post-marketing experience d Frequencies derived from lab observations (Uric acid increases to >upper limit of normal from baseline below or within reference range. Creatinine increases of >50% from baseline.) and not crude adverse event report frequency.

e e.g. conjunctival, retinal, intraocular bleeding f e.g. epistaxis, haemoptysis g e.g. gingival bleeding, rectal haemorrhage, gastric ulcer haemorrhage h e.g. ecchymosis, skin haemorrhage, petechiae i e.g. haemarthrosis, muscle haemorrhage j e.g. haematuria, cystitis haemorrhagic k e.g. vaginal haemorrhage, haematospermia, postmenopausal haemorrhage l e.g. contusion, traumatic haematoma, traumatic haemorrhage m i.e. spontaneous, procedure related or traumatic intracranial haemorrhage

Description of selected adverse reactions

Bleeding
Bleeding findings in PLATO
Overall 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 daily
N=9235
Clopidogrel

N=9186

p-value*
PLATO Total Major

Summary of the safety profile
The 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 reactions
The 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 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)

SOC
Very common

Common

Uncommon

Not known
Neoplasms benign, malignant and unspecified
(including cysts and polyps)

Tumour bleedingsa

SOC
Very common

Common

Uncommon

Not known
Blood and lymphatic system disorders
Blood disorder bleedingsb

Thrombotic
Thrombocytopenic
Purpurac
Immune system disorders

Hypersensitivity including angioedemac

Metabolism and nutrition disorders
Hyperuricaemiad
Gout/Gouty
Arthritis

Psychiatric disorders

Confusion

Nervous system disorders

Dizziness,
Syncope,
Headache
Intracranial haemorrhagem

Eye disorders

Eye haemorrhagee

Ear and labyrinth disorders

Vertigo
Ear haemorrhage

Cardiac disorders

Bradyarrhythmia,
AV blockc
Vascular disorders

Hypotension

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

SOC
Very common

Common

Uncommon

Not known
Injury, poisoning and procedural complications

Post procedural haemorrhage,
Traumatic bleedingsl

a e.g. bleeding from bladder cancer, gastric cancer, colon cancer b e.g. increased tendency to bruise, spontaneous haematoma, haemorrhagic diathesis c Identified in post-marketing experience d Frequencies derived from lab observations (Uric acid increases to >upper limit of normal from baseline below or within reference range. Creatinine increases of >50% from baseline.) and not crude adverse event report frequency.
e e.g. conjunctival, retinal, intraocular bleeding f e.g. epistaxis, haemoptysis g e.g. gingival bleeding, rectal haemorrhage, gastric ulcer haemorrhage h e.g. ecchymosis, skin haemorrhage, petechiae i e.g. haemarthrosis, muscle haemorrhage j e.g. haematuria, cystitis haemorrhagic k e.g. vaginal haemorrhage, haematospermia, postmenopausal haemorrhage l e.g. contusion, traumatic haematoma, traumatic haemorrhage m i.e. spontaneous, procedure related or traumatic intracranial haemorrhage

Description of selected adverse reactions

Bleeding
Bleeding findings in PLATO
Overall 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 daily
N=9235
Clopidogrel
N=9186

p-value*
PLATO Total Major

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) or who are at increased risk of trauma. 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.

In two randomised controlled studies (TICO and TWILIGHT) in patients with ACS who have undergone a PCI procedure with a drug-eluting stent, discontinuing ASA after 3 months dual antiplatelet therapy with ticagrelor and ASA (DAPT), and continuing with ticagrelor as single antiplatelet therapy (SAPT) for 9 and 12 months, respectively, has been shown to decrease the risk of bleeding with no observed increase in risk of major adverse cardiovascular events (MACE) compared with continued DAPT. The decision to discontinue ASA after 3 months and continue with ticagrelor as single antiplatelet therapy for 9 months in patients with an increased risk of bleeding should be based on clinical judgment considering the risk of bleeding versus the risk of thrombotic events (see section 4.2).

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 5 days prior to surgery (see section 5.1).

Patients with prior ischaemic stroke
ACS patients with prior ischaemic stroke can be treated with ticagrelor 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
Holter ECG monitoring has shown an increased frequency of mostly asymptomatic ventricular pauses during treatment with ticagrelor compared with clopidogrel. 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) have been 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).

Bradyarrhythmic events and AV blocks have been reported in the post-marketing setting in patients taking ticagrelor (see section 4.8), primarily in patients with ACS, where cardiac ischemia and concomitant drugs reducing the heart rate or affecting cardiac conduction are potential confounders.
The patient’s clinical condition and concomitant medication should be assessed as potential causes prior to adjusting treatment.

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.

Central sleep apnoea
Central sleep apnoea including Cheyne-Stokes respiration has been reported in the post-marketing setting in patients taking ticagrelor. If central sleep apnoea is suspected, further clinical assessment should be considered.

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.

Thrombotic Thrombocytopenic Purpura (TTP)
Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely with the use of ticagrelor. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.

Interference with platelet function tests to diagnose heparin induced thrombocytopenia (HIT) In the heparin induced platelet activation (HIPA) test used to diagnose HIT, anti-platelet factor 4/heparin antibodies in patient serum activate platelets of healthy donors in the presence of heparin.

False negative results in a platelet function test (to include, but may not be limited to the HIPA test) for HIT have been reported in patients administered ticagrelor. This is related to inhibition of the P2Y12-receptor on the healthy donor platelets in the test by ticagrelor in the patient’s sera/plasma.
Information on concomitant treatment with ticagrelor is required for interpretation of HIT platelet function tests.

In patients who have developed HIT, the benefit-risk of continued treatment with ticagrelor should be assessed, taking both the prothrombotic state of HIT and the increased risk of bleeding with concomitant anticoagulant and ticagrelor treatment into consideration.

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, MI or stroke due to the patient’s underlying disease.
Therefore, premature discontinuation of treatment should be avoided.

Sodium
Brilique contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially ‘sodium-free’.

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. Ticagrelor is a breast cancer resistance protein (BCRP) inhibitor.

Effects of medicinal and other products on ticagrelor

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

CYP3A inducers
Co-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.

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 delayed and decreased exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolite, has been observed in patients with ACS treated with morphine (35% reduction in ticagrelor exposure). This interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical relevance is unknown, but data indicate the potential for reduced ticagrelor efficacy in patients co-administered ticagrelor and morphine. In patients with ACS, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered.

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 reactions 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 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.

Rosuvastatin (BCRP substrate)
Ticagrelor has been shown to increase rosuvastatin Cmax by approximately 2.5-fold and AUC by approximately 2.4-fold, which may result in increased risk of myopathy, including rhabdomyolysis.
Consideration should be given to the benefits of prevention of major adverse cardiovascular events by use of rosuvastatin versus the risks with increased rosuvastatin plasma concentrations.

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.

Ticagrelor is well tolerated in single doses up to 900 mg. Gastrointestinal toxicity was dose-limiting in a single ascending dose study. Other clinically meaningful adverse reactions which may occur with overdose include dyspnoea and ventricular pauses (see section 4.8).

In the event of an overdose, the above potential adverse reactions could occur and ECG monitoring should be considered.

There is currently no known antidote to reverse the effects of ticagrelor, and ticagrelor is not dialysable (see section 5.2). Treatment of overdose should follow local standard medical practice. The expected effect of excessive ticagrelor dosing is prolonged duration of bleeding risk associated with platelet inhibition. Platelet transfusion is unlikely to be of clinical benefit in patients with bleeding (see section 4.4). If bleeding occurs other appropriate supportive measures should be taken.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin, ATC code: B01AC24

Mechanism of action
Brilique 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.

Pharmacodynamic effects
Onset of action
In 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 action
If a CABG procedure is planned, ticagrelor bleeding risk is increased compared to clopidogrel when discontinued within less than 96 hours prior to procedure.

Switching data
Switching 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 safety
The 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)

Ticagrelor demonstrates linear pharmacokinetics and exposure to ticagrelor and the active metabolite (AR-C124910XX) are approximately dose proportional up to 1260 mg.

Absorption
Absorption 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).

Distribution

Ticagrelor demonstrates linear pharmacokinetics and exposure to ticagrelor and the active metabolite (AR-C124910XX) are approximately dose proportional up to 1260 mg.

Absorption
Absorption 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 orodispersible tablets, dispersed in saliva and swallowed without water or suspended in water and administered through a nasogastric tube into the stomach, were bioequivalent to film-coated whole tablets (AUC and Cmax within 80-125% for ticagrelor and the active metabolite). When the orodispersible tablet was dispersed in saliva and swallowed with water, ticagrelor AUC was similar, while Cmax was about 15% lower than for the film-coated tablet. The small difference in Cmax noted is unlikely to be of clinical relevance.