4.1. Therapeutic indications

Ticagrelor Tablets, 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).

4.2. Posology and method of administration

Posology

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

Acute coronary syndromes

Ticagrelor Tablets 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 Ticagrelor 90 mg Tablets twice daily is recommended for 12 months in ACS patients unless discontinuation is clinically indicated (see section 5.1).

History of myocardial infarction

Ticagrelor 60 mg Tablets 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 initia l one- year treatment with Ticagrelor 90 mg Tablets 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 Ticagrelor Tablets 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 Ticagrelor Tablets 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.

Ticagrelor Tablets 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.

4.3. Contraindications

• 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).

4.4. Special warnings and precautions for use

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 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 thesepatients.

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).

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 isdiscouraged.

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 Ticagrelor Tablets, 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

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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 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 (3x200 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 ofcyclosporine.

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.

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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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 𝒞1/10), uncommon (≥1/1,000 to 𝒞1/100), rare (≥1/10,000 to 𝒞1/1,000), 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

Metabolism and nutrition disorders

Hyperuricaemiad

Gout/Gouty Arthritis

Psychiatric disorders

Confusion

Nervous system disorders

Dizziness, Syncope, Headache

Intracranial haemorrhage

Eye disorders

Eye haemorrhagee

Ear and labyrinth disorders

Vertigo

Ear haemorrhage

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

ae.g. bleeding from bladder cancer, gastric cancer, colon cancer

be.g. increased tendency to bruise, spontaneous haematoma, haemorrhagic diathesis

cIdentified in post-marketing experience

dFrequencies 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.

ee.g. conjunctival, retinal, intraocular bleeding

fe.g. epistaxis, haemoptysis

ge.g. gingival bleeding, rectal haemorrhage, gastric ulcer haemorrhage

he.g. ecchymosis, skin haemorrhage, petechiae

ie.g. haemarthrosis, muscle haemorrhage

je.g. haematuria, cystitis haemorrhagic

ke.g. vaginal haemorrhage, haematospermia, postmenopausal haemorrhage

le.g. contusion, traumatic haematoma, traumatic 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 90mg

twice daily

N=9235

Clopidogrel

N=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

𝒞0.0001

TIMI-defined Major

7.9

7.7

0.5669

TIMI-defined Major + Minor

11.4

10.9

0.3272

Bleeding category definitions:

Major Fatal/Life-threatening Bleed: Clinically apparent with >50 g/L decrease in haemoglobin or ≥4 red cell units transfused; or fatal; or intracranial; or intrapericardial with cardiac tamponade; or with hypovolaemic shock or severe hypotension requiring pressors or surgery. Major Other: Clinically apparent with 30-50 g/L decrease in haemoglobin or 2-3 red cell units transfused; or significantly disabling.

Minor Bleed: Requires medical intervention to stop or treat bleeding. TIMI Major Bleed: Clinically apparent with >50 g/Ldecrease in haemoglobin orintracranial haemorrhage.

TIMI Minor Bleed: Clinically apparent with 30-50 g/L decrease in haemoglobin.

*p-value calculated from Cox proportional hazards model with treatment group as the only explanatory variable.

Ticagrelor and clopidogrel did not differ in rates of PLATO Major Fatal/Life- threatening bleeding, PLATO total Major bleeding, TIMI Major bleeding, or TIMI Minor bleeding (Table 2). However, more PLATO combined Major + Minor bleeding occurred with ticagrelor compared with clopidogrel. Few patients in PLATO had fatal bleeds: 20 (0.2%) for ticagrelor and 23 (0.3%) for clopidogrel (see section 4.4).

Age, sex, weight, race, geographic region, concurrent conditions, concomitant therapy and medical history, including a previous stroke or transient ischaemic attack, all did not predict either overall or non-procedural PLATO Major bleeding. Thus, no particular group was identified at risk for any subset of bleeding.

CABG-related bleeding:

In PLATO, 42% of the 1584 patients (12% of cohort) who underwent coronary artery bypass graft (CABG) surgery had a PLATO Major Fatal/Life-threatening bleeding with no difference between treatment groups. Fatal CABG bleeding occurred in 6 patients in each treatment group (see section 4.4).

Non-CABG related bleeding and non-procedural related bleeding:

Ticagrelor and clopidogrel did not differ in non-CABG PLATO-defined Major Fatal/Life- threatening bleeding, but PLATO-defined Total Major, TIMI Major, and TIMI Major + Minor bleeding were more common with ticagrelor. Similarly, when removing all procedure related bleeds, more bleeding occurred with ticagrelor than with clopidogrel (Table 2). Discontinuation of treatment due to non- procedural bleeding was more common for ticagrelor (2.9%) than for clopidogrel (1.2%; p<0.001).

Intracranial bleeding:

There were more intracranial non-procedural bleeds with ticagrelor (n=27 bleeds in 26 patients, 0.3%) than with clopidogrel (n=14 bleeds, 0.2%), of which 11 bleeds with ticagrelor and 1 with clopidogrel were fatal. There was no difference in overall fatal bleeds.

Bleeding findings in PEGASUS

Overall 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 + ASA

N=6958

ASA Alone

N=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

Bleeding category definitions:

TIMI Major: Fatal bleeding, OR any intracranial bleeding, OR clinically overt signs of haemorrhage associated with a drop in haemoglobin (Hgb) of ≥50 g/L, or when Hgb is not available, a fall in haematocrit (Hct) of 15%. Fatal: A bleeding event that directly led to death within 7 days.

ICH: Intracranial haemorrhage.

Other TIMI Major: Non-fatal non-ICH TIMI Major bleeding.

TIMI Minor: Clinically apparent with 30-50 g/Ldecrease in haemoglobin.

TIMI Requiring medical attention: Requiring intervention, OR leading to hospitalisation, OR prompting evaluation. PLATO Major Fatal/life- threatening: Fatal bleeding, OR any intracranial bleeding, OR intrapericardial with cardiac tamponade, OR with hypovolaemic shock or severe hypotension requiring pressors/inotropes or surgery OR clinically apparent with >50 g/L decrease in haemoglobin or ≥4 red cell units transfused.

PLATO Major Other: Significantly disabling, OR clinically apparent with 30-50 g/L decrease in haemoglobin, OR 2-3 red cell units transfused.

PLATO Minor: Requires medical intervention to stop or treat bleeding.

In PEGASUS, TIMI Major bleeding for ticagrelor 60 mg twice daily was higher than for ASA alone. No increased bleeding risk was seen for fatal bleeding and only a minor increase was observed in intracranial haemorrhages, as compared to ASA therapy alone. There were few fatal bleeding events in the study, 11 (0.3%) for ticagrelor 60 mg and 12 (0.3%) for ASA therapy alone. The observed increased risk of TIMI Major bleeding with ticagrelor 60 mg was primarily due to a higher frequency of Other TIMI Major bleedings driven by events in the gastrointestinal SOC.

Increased bleeding patterns similar to TIMI Major were seen for TIMI Major or Minor and PLATO Major and PLATO Major or Minor bleeding categories (see Table 3). Discontinuation of treatment due to bleeding was more common with ticagrelor 60 mg compared to ASA therapy alone (6.2% and 1.5%, respectively). The majority of these bleedings were of less severity (classified as TIMI Requiring medical attention), e.g. epistaxis, bruising and haematomas.

The bleeding profile of ticagrelor 60 mg was consistent across multiple pre- defined subgroups (e.g. by age, gender, weight, race, geographic region, concurrent conditions, concomitant therapy and medical history) for TIMI Major, TIMI Major or Minor and PLATO Major bleeding events.

Intracranial bleeding:

Spontaneous ICHs were reported in similar rates for ticagrelor 60 mg and ASA therapy alone (n=13, 0.2% in both treatment groups). Traumatic and procedural ICHs showed a minor increase with ticagrelor 60 mg treatment, (n=15, 0.2%) compared with ASA therapy alone (n=10, 0.1%). There were 6 fatal ICHs with ticagrelor 60 mg and 5 fatal ICHs with ASA therapy alone. The incidence of intracranial bleeding was low in both treatment groups given the significant comorbidity and CV risk factors of the population under study.

Dyspnoea

Dyspnoea, a sensation of breathlessness, is reported by patients treated with ticagrelor. 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 section4.4).

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 ticagrelor, 0.9% of patients discontinued study drug because of dyspnoea compared with 0.1% taking clopidogrel. The higher incidence of dyspnoea with ticagrelor is not associated with new or worsening heart or lung disease (see section 4.4). Ticagrelor 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.

Investigations

Uric 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 reactions

Reporting 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 Yellow Card Scheme on the MHRA website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.