Possia

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



2 

1. NAME OF THE MEDICINAL PRODUCT 

 

Possia 90 mg film coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each film coated tablet contains 90 mg ticagrelor. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Film-coated tablet (tablet). 

 

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

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Possia, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of 

atherothrombotic events in adult patients with Acute Coronary Syndromes (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). 

 

For further information, please refer to section 5.1. 

 

4.2 Posology and method of administration 

 

Posology 

Possia treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then 

continued at 90 mg twice daily. 

 

Patients taking Possia should also take ASA daily, unless specifically contraindicated. Following an 

initial dose of ASA, Possia should be used with a maintenance dose of ASA of 75-150 mg (see 

section 5.1). 

 

Treatment is recommended for up to 12 months unless discontinuation of Possia is clinically indicated 

(see section 5.1). Experience beyond 12 months is limited. 

 

In patients with Acute Coronary Syndromes (ACS), premature discontinuation with any antiplatelet 

therapy, including Possia, could result in an increased risk of cardiovascular death, or myocardial 

infarction due to the patient’s underlying disease. Therefore, premature discontinuation of treatment 

should be avoided. 

 

Lapses in therapy should also be avoided. A patient who misses a dose of Possia should take only one 

90 mg tablet (their next dose) at its scheduled time. 

 

Patients treated with clopidogrel can be directly switched to Possia if needed (see section 5.1). 

Switching from prasugrel to Possia has not been investigated. 

 

Special populations 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



3 

Elderly  patients 

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

 

Patients with renal impairment 
No dose adjustment is necessary for patients with renal impairment (see section 5.2). No information 

is available concerning treatment of patients on renal dialysis and therefore Possia is not recommended 

in these patients. 

 

Patients with hepatic impairment 
No dose adjustment is necessary for patients with mild hepatic impairment. Possia has not been 

studied in patients with moderate or severe hepatic impairment. Its use in patients with moderate to 

severe hepatic impairment is therefore contraindicated (see section 4.3, 4.4 and 5.2). 

 

Paediatric patients 
The safety and efficacy of Possia in children below the age of 18 in the approved adult indication has 

not been established. No data are available (see section 5.1 and 5.2). 

 

Method of administration  

For oral use. Possia can be administered with or without food. 

 

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). 

 Moderate to severe hepatic impairment (see section 4.2, 4.4 and 5.2). 

 Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g., ketoconazole, 
clarithromycin, nefazodone, ritonavir, and atazanavir) is contraindicated, as co-administration 

may lead to a substantial increase in exposure to ticagrelor (see section 4.4 and 4.5). 

 

4.4 Special warnings and precautions for use 

 

Bleeding risk 

In the phase 3 pivotal trial (PLATO [PLATelet Inhibition and Patient Outcomes], 18,624 patients) key 

exclusion criteria included an increased risk for bleeding, clinically important thrombocytopenia or 

anaemia, previous intracranial bleed, gastrointestinal bleed within the past 6 months or major surgery 

within the past 30 days. Patients with acute coronary syndromes treated with Possia and ASA showed 

an increased risk of non-CABG major bleeding and also more generally in bleeds requiring medical 

attention i.e. Major + Minor PLATO bleeds, but not Fatal or Life-threatening bleeds (see section 4.8). 

 

Therefore, the use of Possia in patients at known increased risk for bleeding should be balanced 

against the benefit in terms of prevention of atherothrombotic events. If clinically indicated, Possia 

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 Possia is contraindicated in 

patients with active pathological bleeding, in those with a history of intracranial haemorrhage, 

and in patients with moderate to 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 Possia dosing. 

 

No data exist with Possia regarding a haemostatic benefit of platelet transfusions; circulating Possia 

may inhibit transfused platelets. Since co-administration of Possia with desmopressin did not decrease 

template-bleeding time, desmopressin is unlikely to be effective in managing clinical bleeding events 

(see section 4.5). 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



4 

Antifibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa may 

increase haemostasis. Possia 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 Possia before any 

surgery is scheduled and before any new medicinal product is taken. 

 
In PLATO patients undergoing coronary artery bypass grafting (CABG), Possia 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, Possia should be 

discontinued 7 days prior to surgery (see section 5.1). 

 

Patients at risk for bradycardic events 

Due to observations of mostly asymptomatic ventricular pauses in an earlier clinical study, patients 

with an increased risk of bradycardic events (e.g. patients without a pacemaker who have sick sinus 

syndrome, 2nd or 3rd degree AV block or bradycardic-related syncope) were excluded from the main 

PLATO study evaluating the safety and efficacy of Possia. Therefore, due to the limited clinical 

experience, Possia should be used with caution in these patients (see section 5.1). 

 

In addition, caution should be exercised when administering Possia 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 by 13.8% of patients treated with Possia and by 7.8% of patients treated with 

clopidogrel. In 2.2% of patients, investigators considered the dyspnoea causally related to treatment 

with Possia. It is usually mild to moderate in intensity and often resolves without need for treatment 

discontinuation. Patients with asthma/COPD may have an increased absolute risk of experiencing 

dyspnoea with Possia (see section 4.8). 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 Possia 

should be stopped. 

 

Creatinine elevations 

Creatinine levels may increase during treatment with Possia (see section 4.8). The mechanism has not 

been elucidated. Renal function should be checked after one month and thereafter according to routine 

medical practice, paying special attention to patients ≥ 75 years, patients with moderate/severe renal 

impairment and those receiving concomitant treatment with an ARB. 

 

Uric acid increase 

In PLATO study, patients on ticagrelor had a higher risk of hyperuricaemia than those patients 

receiving clopidogrel (see section 4.8). Caution should be exercised when administering ticagrelor to 

patients with history of hyperuricaemia or gouty arthritis. As a precautionary measure, the use of 

ticagrelor in patients with uric acid nephropathy is discouraged. 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



5 

Other 

Based on a relationship observed in PLATO between maintenance ASA dose and relative efficacy of 

ticagrelor compared to clopidogrel, co-administration of Possia and high maintenance dose ASA 

(>300 mg) is not recommended (see section 5.1). 

 

Co-administration of Possia with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, 

nefazodone, ritonavir, and atazanavir) is contraindicated (see section 4.3 and 4.5). Co-administration 

may lead to a substantial increase in Possia exposure (see section 4.5). 

 

Co-administration of ticagrelor with strong CYP3A4 inducers (e.g. rifampicin, dexamethasone, 

phenytoin, carbamazepine and phenobarbital) is discouraged, as co-administration may lead to a 

decrease in exposure and efficacy of ticagrelor (see section 4.5). 

 

Co-administration of Possia and CYP3A4 substrates with narrow therapeutic indices (i.e., cisapride 

and ergot alkaloids) is not recommended, as ticagrelor may increase the exposure to these medicinal 

products (see section 4.5). The concomitant use of Possia with doses of simvastatin or lovastatin 

greater than 40 mg is not recommended (see section 4.5). 

 

Close clinical and laboratory monitoring is recommended when giving digoxin concomitantly with 

Possia (see section 4.5). 

 

No data are available on concomitant use of Possia with potent P-glycoprotein (P-gp) inhibitors (e.g. 

verapamil, quinidine, cyclosporin) that may increase ticagrelor exposure. If the association cannot be 

avoided, their concomitant use should be made with caution (see section 4.5). 

 

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-gp 

substrate and a weak P-gp inhibitor and may increase the exposure of P-gp substrates. 

 

Effects of other medicinal products on Possia 

 

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 their concomitant use with Possia is contraindicated (see section 4.3 and 4.4). 

 

 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 Possia.  

 

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. dexamethasone, phenytoin, carbamazepine and 

phenobarbital) would be expected to decrease the exposure to Possia as well. Co-administration of 

ticagrelor with potent CYP3A inducers may decrease exposure and efficacy of ticagrelor  (see 

section 4.4). 

 
Others 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



6 

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 Possia (see section 4.4). 

 

No data are available on concomitant use of Possia with potent P-gp inhibitors (e.g. verapamil, 

quinidine, cyclosporin) that may increase ticagrelor exposure. If clinically indicated, their concomitant 

use should be made with caution (see section 4.4). 

 
Effects of Possia 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. Possia may have similar effect on lovastatin. The concomitant use of Possia with doses 

of simvastatin or lovastatin greater than 40 mg is not recommended (see section 4.4). 

 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 Possia 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 (see section 4.4). 

 
Medicinal products metabolised by CYP2C9 

Co-administration of Possia with tolbutamide resulted in no change in the plasma levels of either 

medicinal product, which suggest 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 Possia 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 Possia. 

 

P-glycoprotein (P-gp) substrates (including digoxin, cyclosporin)  
Concomitant administration of Possia 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 or cyclosporin concomitantly with Possia (see section 4.4). 

 

Other concomitant therapy 

 

Medicinal products known to induce bradycardia 

Due to observations of mostly asymptomatic ventricular pauses and bradycardia, caution should be 

exercised when administering Possia concomitantly with medicinal products known to induce 

bradycardia (see section 4.4). However no evidence of clinically significant adverse reactions was 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



7 

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). 

 

In the PLATO study, Possia was commonly administered with ASA, proton pump inhibitors, statins, 

beta-blockers, angiotensin converting enzyme 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 Possia 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 Possia with medicinal products known to alter haemostasis (see section 4.4). 

 

Due to reports of cutaneous bleeding abnormalities with SSRIs (e.g., paroxetine, sertraline and 

citalopram), caution is advised when administering SSRIs with Possia 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 Possia 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). Possia is not recommended during 

pregnancy. 

 

Breastfeeding  
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 breastfeeding or to discontinue/abstain from Possia therapy 

taking into account the benefit of breastfeeding 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 

 

No studies on the effects of Possia on the ability to drive and use machines have been performed. 

Possia is expected to have no or negligible influence on the ability to drive and use machines.  

 

4.8 Undesirable effects 

 

Summary of safety profile 

The safety of Possia in patients with acute coronary syndromes (UA, NSTEMI and STEMI) was 

evaluated in the pivotal large phase 3 PLATO ([PLATelet Inhibition and Patient Outcomes] study, 

18,624 patients), which compared patients treated with Possia (loading dose of 180 mg of Possia and a 

maintenance dose of 90 mg twice daily) to patients treated with clopidogrel (300-600 mg loading dose 

followed by 75 mg once daily maintenance dose) both given in combination with acetylsalicylic acid 

(ASA) and other standard therapies. 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



8 

The most commonly reported adverse reactions in patients treated with ticagrelor were dyspnoea, 

contusion and epistaxis and these reactions occurred at higher rates than in the clopidogrel treatment 

group. 

 

Tabulated summary of adverse reactions 

The following adverse reactions have been identified following studies with Possia (Table 1). 

 

Adverse reactions are classified according to frequency and System Organ Class. 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) 

 

Common Uncommon Rare 

System Organ Class 

Metabolism and nutrition disorders 

  Hyperuricaemia
a
 

Psychiatric disorders 

  Confusion 

Nervous system disorders 

 Intracranial haemorrhage
b
, 

Dizziness, Headache 

Paraesthesia 

Eye disorders 

 Eye haemorrhage 

(intraocular, conjunctival, 

retinal) 

 

Ear and labyrinth disorders 

  Ear haemorrhage, Vertigo 

Respiratory, thoracic and mediastinal disorders 

Dyspnoea
c
, Epistaxis Haemoptysis  

Gastrointestinal disorders 

Gastrointestinal 

haemorrhage
d
 

Haematemesis, 

Gastroinstestinal ulcer 

haemorrhage
e
, Haemorrhoidal 

haemorrhage, Gastritis, Oral 

haemorrhage (including 

gingival bleeding), Vomiting, 

Diarrhoea, Abdominal pain, 

Nausea, Dyspepsia 

Retroperitoneal haemorrhage, 

Constipation 

Skin and subcutaneous tissue disorders 

Subcutaneous or dermal 

bleeding
f
, Bruising g 

Rash, Pruritus  

Musculoskeletal and connective tissue disorders 

  Haemarthrosis
#
 

Renal and urinary disorders 

 Haemorrhage urinary tract h  

Reproductive system and breast disorders 

 Vaginal bleeding (including 

metrorrhagia) 

 

Investigations 

  Blood creatinine increased 

Injury, poisoning and procedural complications 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



9 

Table 1 – Adverse reactions by frequency and System Organ Class (SOC) 

 

Common Uncommon Rare 

Procedural site haemorrhage
i
 Post procedural haemorrhage, 

Haemorrhage
 

Wound haemorrhage, 

Traumatic haemorrhage 

Immune system disorders 

 Hypersensitivity including 

angioedema 

 

Multiple related adverse reaction terms have been grouped together in the table and include medical terms as 

described below: 
a
 Hyperuricaemia, Blood uric acid increased 

b
 Cerebral haemorrhage, Haemorrhage intracranial, Haemorrhagic stroke,  

c
 Dyspnoea, Dyspnoea exertional, Dyspnoea at rest, Nocturnal dyspnoea  

d
 Gastrointestinal haemorrhage, Rectal haemorrhage, Intestinal haemorrhage, Melaena, Occult blood 

e 
Gastrointestinal ulcer haemorrhage, Gastric ulcer haemorrhage, Duodenal ulcer haemorrhage, Peptic ulcer 

haemorrhage 
f
 Subcutaneous haematoma, Skin haemorrhage, Haemorrhage subcutaneous, Petechiae 

g 
 Contusion, Haematoma, Ecchymosis, Increased tendency to bruise, Traumatic haematoma 

h
 Haematuria, Blood urine present, Haemorrhage urinary tract 

i
 Vessel puncture site haemorrhage, Vessel puncture site haematoma, Injection site haemorrhage, Puncture 

site haemorrhage, Catheter site haemorrhage 
#  

There were no reported ADRs of haemarthrosis reported in the ticagrelor arm (n=9235) of the PLATO 

study, the frequency has been calculated using the upper limit of the 95% confidence interval for the point 

estimate (based on 3/X, where X represents the total sample size e.g. 9235). This is calculated as 

3/9235 which equates to a frequency category of ‘rare’
 

 

Description of selected adverse reactions 

 

Bleeding 

Overall outcome of bleeding rates in the PLATO study are shown in Table 2. 

 

Table 2 –Kaplan-Meier estimate of bleeding rates by treatment 

 

 
Possia 

(%/year) 

N=9235 

Clopidogrel 

(%/year) 

N=9186 

 

 

P 

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 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/l decrease in haemoglobin or intracranial haemorrhage. 

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

 

Possia 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). 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



10 

 

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: Possia 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. 
 

Dyspnoea 

Dyspnoea, a sensation of breathlessness, is reported by patients treated with Possia. 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, chronic obstructive pulmonary disease, or asthma; these patients, and the elderly, were 

more likely to report dyspnoea. For Possia, 0.9% of patients discontinued study drug because of 

dyspnoea compared with 0.1% taking clopidogrel. The higher incidence of dyspnoea with Possia is not 

associated with new or worsening heart or lung disease (see section 4.4). Possia does not affect tests of 

pulmonary function. 

 

Investigations  

Creatinine elevations: In PLATO, serum creatinine concentration significantly increased by >30% in 

25.5% of patients receiving ticagrelor compared to 21.3% of patients receiving clopidogrel and 

by >50% in 8.3% of patients receiving ticagrelor compared to 6.7% of patients receiving clopidogrel. 

Creatinine elevations by >50% were more pronounced in patients > 75 years (ticagrelor 13.6% versus 

clopidogrel 8.8%), in patients with severe renal impairment at baseline (ticagrelor 17.8% versus 

clopidogrel 12.5%) and in patients receiving concomitant treatment with ARBs (ticagrelor 11.2% 

versus clopidogrel 7.1%). Within these subgroups renal-related serious adverse events and adverse 

events leading to discontinuation of study drug were similar between treatment groups. The totality of 

renal AEs reported were 4.9% for ticagrelor vs. 3.8% for clopidogrel, however a similar percent of 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



11 

patients reported events considered by the investigators as causally related to treatment; 54 (0.6%) for 

ticagrelor and 43 (0.5%) for clopidogrel. 

 

Uric acid elevations: In PLATO, serum uric acid concentration increased to more than upper limit of 

normal in 22% of patients receiving ticagrelor compared to 13% of patients receiving clopidogrel. 

Mean serum uric acid concentration 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. The hyperuricaemia AEs reported 

were 0.5% for ticagrelor vs. 0.2% for clopidogrel. Of these AEs 0.05% for ticagrelor vs. 0.02% for 

clopidogrel were considered causally related by investigators. For gouty arthritis, the AEs reported 

were 0.2% for ticagrelor vs 0.1% for clopidogrel; none of these adverse events were assessed as 

causally related by investigators. 

 

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 overdose, observe for these potential adverse reactions and consider ECG monitoring 

 

There is currently no known antidote to reverse the effects of Possia, and Possia is not expected to be 

dialysable (see section 4.4). Treatment of overdose should follow local standard medical practice. The 

expected effect of excessive Possia dosing is prolonged duration of bleeding risk associated with 

platelet inhibition. If bleeding occurs appropriate supportive measures should be taken. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

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

 

Mechanism of action 

Possia contains ticagrelor a member of the chemical class cyclopentyltriazolopyrimidines (CPTP), 

which is a selective adenosine diphosphate (ADP) receptor antagonist acting on the P2Y12 

ADP-receptor that can prevent ADP-mediated platelet activation and aggregation. Ticagrelor is orally 

active, and reversibly interacts with the platelet P2Y12 ADP-receptor. Ticagrelor does not interact with 

the ADP binding site itself, but interacts with platelet P2Y12 ADP-receptor to prevent signal 

transduction. 

 

Pharmacodynamic effects 

Onset of Action 

In patients with stable coronary artery disease 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 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



12 

Switching from clopidogrel to ticagrelor 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 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 coronary artery bypass grafting (CABG) (see section 4.1). 

 

On a background of daily ASA, ticagrelor 90 mg twice daily showed superiority to 75 mg daily 

clopidogrel in preventing the composite endpoint of cardiovascular [CV] death, myocardial infarction 

[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 for up 

to 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 3). 

 

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 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 Possia 

should be 75-150 mg (see section 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. 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



13 

 
 

 

Figure 1 – Time to first occurrence of CV death, MI and Stroke (PLATO) 

 

Possia reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the 

UA/NSTEMI and STEMI population (Table 3). 

 

Table 3 -Outcome Events in PLATO 

 Possia 

(% patients 

with event) 

N=9333 

Clopidogrel 

(% patients 

with event) 

N=9291 

 

 

ARR
a 

(%/yr) 

 

 

RRR
a
 (%) 

(95% CI) 

 

 

 

P 

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) 0.0444
d
 

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 ATE
c 

 

 

13.8 

 

 

15.7 

 

 

2.1 

 

 

12 (5, 19) 

 

 

0.0006 

 All-cause 

mortality 

 

4.3 

 

5.4 

 

1.4 

 

22 (11, 31) 

 

0.0003
d
 

Definite stent 

thrombosis 

 

1.2 

 

1.7 

 

0.6 

 

32 (8, 49) 

 

0.0123
d 

aARR = absolute risk reduction; RRR = relative risk reduction = (1-Hazard ratio) x 100%. A negative RRR indicates a 

relative risk increase. 
bexcluding silent myocardial infarction. 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



14 

cSRI = serious recurrent ischaemia; RI = recurrent ischaemia; TIA = transient ischaemic attack; ATE = arterial thrombotic 

event. Total MI includes silent MI, with date of event set to date when discovered. 
dnominal significance value; all others are formally statistically significant by pre-defined hierarchical testing. 

 

Holter Substudy 

To 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. 

 

PLATO genetic substudy 

CYP2C19 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 composite 

A combined efficacy and safety composite (CV death, MI, stroke, or PLATO-defined ‘Total Major’ 

bleeding) indicates that the benefit in efficacy of Possia 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. 

 

Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with Possia 

in all subsets of the paediatric population in the granted indication (see section 4.2 and 5.2). 

 

5.2 Pharmacokinetic properties 

 

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 oral administration of ticagrelor 90 mg under fasted conditions, 

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 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. 

 

Distribution 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



15 

The 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%). 

 

Biotransformation 

CYP3A4 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. 

 

Elimination 
The primary route of ticagrelor elimination is via hepatic metabolism. When radiolabeled 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. 

 
Special populations 

 

Elderly 

Higher 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 

Ticagrelor has not been evaluated in a paediatric population (see section 4.2 and 5.1). 

 

Gender 
Higher exposures to ticagrelor and the active metabolite were observed in women compared to men. 

These differences are not considered clinically significant. 

 

Renal impairment 
Exposure to ticagrelor and the active metabolite were approximately 20% lower in patients with severe 

renal impairment (creatinine clearance <30 ml/min) compared to subjects with normal renal function 

(see section 4.2). 

 

Hepatic impairment 
Cmax and AUC for ticagrelor were 12% and 23% higher in patients with mild hepatic impairment 

compared to matched healthy subjects, respectively (see section 4.2). Ticagrelor has not been studied 

in patients with moderate or severe hepatic impairment and its use in these patients is contraindicated 

(see section 4.3 and 4.4). 

 

Ethnicity 
Patients 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. 

 

5.3 Preclinical safety data 

 

Preclinical data for ticagrelor and its major metabolite have not demonstrated unacceptable risk for 

adverse effects for humans based on conventional studies of safety pharmacology, single and repeated 

dose toxicity and genotoxic potential. 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



16 

 

Gastrointestinal irritation was observed in several animal species at clinical relevant exposure levels 

(see section 4.8). 

 

In female rats, ticagrelor at high dose showed an increased incidence of uterine tumors 

(adenocarcinomas) and an increased incidence of hepatic adenomas. The mechanism for uterine 

tumors is likely hormonal imbalance which can lead to tumors in rats. The mechanism for the hepatic 

adenomas is likely due to a rodent-specific enzyme induction in the liver. Thus, the carcinogenicity 

findings are considered unlikely to be relevant for humans. 

 

In rats minor developmental anomalies were seen at a maternal toxic dose (safety margin of 5.1). In 

rabbits a slight delay in hepatic maturity and skeletal development was seen in foetuses from dams at 

high dose without showing maternal toxicity (safety margin of 4.5). 

 

Studies in rats and rabbits have shown reproductive toxicity, with slightly reduced maternal body 

weight gain and reduced neonatal viability and birth weight, with delayed growth. Ticagrelor produced 

irregular cycles (mostly extended cycles) in female rats, but did not affect overall fertility in male and 

female rats. Pharmacokinetic studies performed with radio-labeled ticagrelor have shown that the 

parent compound and its metabolites are excreted in the milk of rats (see section 4.6). 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Core 

Mannitol (E421) 

Dibasic calcium phosphate 

Magnesium stearate (E470b) 

Sodium starch glycolate 

Hydroxypropyl-cellulose (E463) 
 

Coating  

Talc 

Titanium dioxide (E171) 

Ferric oxide yellow (E172) 

Polyethylene-glycol 400 

Hypromellose (E464) 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

3 years 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special storage conditions. 

 

6.5 Nature and contents of container 

 

 PVC-PVDC/Al transparent blister (with sun/moon symbols) of 10 tablets; cartons of 60 tablets 
(6 blisters) and 180 tablets (18 blisters). 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



17 

 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. 

 

6.6 Special precautions for disposal 

 

No special requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 
AstraZeneca AB 

S-151 85 

Södertälje 

Sweden 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/10/656/001-006 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation:  3 December 2010 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d

http://www.ema.europa.eu/


18 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 

RELEASE 

 

B.  

 CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



19 

A.  MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer(s) responsible for batch release 

 
AstraZeneca AB 

Gärtunavägen 

SE-151 85 Södertälje 

Sweden 

 

or 

 

AstraZeneca UK Limited 

Silk Road Business Park 

Macclesfield, Cheshire, SK10 2NA 

United Kingdom 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

  

 
Medicinal product subject to medical prescription. 

 

 

C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 

 

Pharmacovigilance system 

The MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1 of the 

Marketing Authorisation, is in place and functioning before and whilst the medicinal product is 

on the market. 

 

Risk Management Plan (RMP) 

The MAH  shall perform the pharmacovigilance activities detailed in the Pharmacovigilance 

Plan, as agreed in the RMP presented in Module 1.8.2 of the Marketing Authorisation and any 

subsequent updates of the RMP agreed by the Committee for Medicinal Products for Human 

Use (CHMP). 

 

As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the 

updated RMP should be submitted at the same time as the next Periodic Safety Update Report 

(PSUR). 

 

In addition, an updated RMP should be submitted: 

 When new information is received that may impact on the current Safety Specification, 

Pharmacovigilance Plan or risk minimisation activities 

 Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being 

reached 

 At the request of the European Medicines Agency. 

 

 

 CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



20 

Not applicable. 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



21 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



22 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



23 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON OF 90 mg FILM-COATED TABLETS 

 

1. NAME OF THE MEDICINAL PRODUCT 

 
Possia 90 mg film-coated tablets 

ticagrelor 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 90 mg ticagrelor 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 
14 film-coated tablets 

56 film-coated tablets 

60 film-coated tablets 

100x1 film-coated tablets 

168 film-coated tablets 

180 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



24 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 
AstraZeneca AB 

S-151 85 

Södertälje 

Sweden 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 
EU/1/10/656/001 60 film-coated tablets 

EU/1/10/656/002 180 film-coated tablets 

EU/1/10/656/003 14 film-coated tablets 

EU/1/10/656/004 56  film-coated tablets 

EU/1/10/656/005 168  film-coated tablets 

EU/1/10/656/006 100x1 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Possia 90 mg 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



25 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

PERFORATED UNIT DOSE BLISTER (100X1 TABLETS) 

 

1. NAME OF THE MEDICINAL PRODUCT 

 
Possia 90 mg tablets 

ticagrelor 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

AstraZeneca AB 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



26 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER (10 TABLETS) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 
Possia 90 mg tablets 

ticagrelor 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

AstraZeneca AB 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

Sun/Moon symbol 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



27 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

CALENDAR BLISTER (14 TABLETS) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 
Possia 90 mg tablets 

ticagrelor 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

AstraZeneca AB 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

Mon Tue Wed Thu Fri Sat Sun 

Sun/Moon symbol 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



28 

  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



29 

 

Package leaflet: Information for the user 
 

Possia 90 mg film-coated tablets 
ticagrelor 

 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their  signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. 
 

What is in this leaflet 
1. What Possia is and what it is used for 

2. What you need to know before you take Possia 

3. How to take Possia 

4. Possible side effects 

5. How to store Possia 
6.  Contents of the pack and other information 

 

 

1.  What Possia is and what it is used for  
 

What Possia is 

Possia contains the active substance called ticagrelor. This belongs to a group of medicines called 

anti-platelet medicines. 

 

How Possia works 

Possia affects cells called ‘platelets’ (also called thrombocytes). These very small blood cells help stop 

bleeding by clumping together to plug tiny holes in blood vessels that are cut or damaged.  
 

However, platelets can also form clots inside diseased blood vessels in the heart and brain. This can be 

very dangerous because: 

 the clot can cut off the blood supply completely - this can cause a heart attack (myocardial 

infarction) or stroke, or 

 the clot can partly block the blood vessels to the heart - this reduces the blood flow to the heart 
and can cause chest pain which comes and goes (called ‘unstable angina’). 

 

Possia helps stop the clumping of platelets. This reduces the chance of a blood clot forming that can 

reduce blood flow. 

 

What Possia is used for 

Possia is to be used in adults only. You have been given Possia because you have had: 

 a heart attack, or 

 unstable angina (angina or chest pain that is not well controlled). 

Possia reduces the chances of you having another heart attack or a stroke or of dying from a disease 

related to your heart or blood vessels. 
 

 

2. What you need to know before you take Possia 

 

Do not take Possia if: 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



30 

 You are allergic (hypersensitive) to ticagrelor or any of the other ingredients of Possia (listed in 
section 6). 

 You are bleeding now or have bled recently inside your body, such as bleeding in your stomach 

or gut from an ulcer. 

 You have moderate to severe liver disease 

 You are taking any of the following medicines: ketoconazole (used to treat fungal infections), 
clarithromycin (used to treat bacterial infections), nefazodone (an antidepressant), ritonavir and 

atazanavir (used to treat HIV infection and AIDS). 

 You have had a stroke caused by bleeding in the brain. 
Do not take Possia if any of the above applies to you. If you are not sure, talk to your doctor or 

pharmacist before taking Possia. 

 

 

Warnings and precautions 
Check with your doctor, pharmacist or dentist before taking Possia if: 

 You have an increased risk of bleeding because of: 

- a recent serious injury 

- recent surgery (including dental work) 

- you have a condition that affects blood clotting 

- recent bleeding from your stomach or gut (such as a stomach ulcer or colon ‘polyps’) 

 You are due to have surgery (including dental work) at any time while taking Possia. This is 

because of the increased risk of bleeding. Your doctor may want you to stop taking Possia 7 

days prior to surgery. 

 Your heart rate is abnormally low (usually lower than 60 beats per minute) and you do not 

already have in place a device that paces your heart (pacemaker). 

 You have asthma or other lung problem or breathing difficulties. 

 You have had a blood test that showed more than the usual amount of uric acid 
 

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or dentist before 

taking Possia. 

 

Children 

Possia is not recommended for children and adolescents under 18 years. 

 

Other medicines and Possia 
Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines. This includes medicines that you buy without a prescription, dietary supplements and 

herbal remedies. This is because Possia can affect the way some medicines work and some medicines 

can have an effect on Possia. 

 

Tell your doctor or pharmacist if you are taking any of the following medicines: 

 more than 40 mg daily of either simvastatin or lovastatin (medicines used to treat high 
cholesterol) 

 rifampicin (an antibiotic), phenytoin, carbamazepine and phenobarbital (used to control 
seizures), dexamethasone (used to treat inflammatory and auto immune conditions), digoxin 

(used to treat heart failure), cyclosporin (used to lessen your body’s defenses), quinidine and 

diltiazem (used to treat abnormal heart rhythms), beta blockers and verapamil (used to treat high 

blood pressure). 

 

In particular, tell your doctor or pharmacist if you are taking any of the following medicines that 

increase your risk of bleeding: 

 ‘oral anticoagulants’ often referred to as ’blood thinners’ which include warfarin. 

 non-steroidal anti-inflammatory drugs (abbreviated as NSAIDs) often taken as pain killers such 
as ibuprofen and naproxen. 

 selective serotonin reuptake inhibitors (abbreviated as SSRIs) taken as antidepressants such as 
paroxetine, sertraline and citalopram 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



31 

 other medicines such as ketoconazole (used to treat fungal infections), clarithromycin (used to 
treat bacterial infections), nefazodone, (an antidepressant), ritonavir and atazanavir (used to treat 

HIV infection and AIDS), cisapride (used to treat heartburn), ergot alkaloids (used to treat 

migraines and headaches). 

 

Also tell your doctor that because you are taking Possia, you may have an increased risk of bleeding if 

your doctor gives you fibrinolytics, often called ‘clot dissolvers’, such as streptokinase or alteplase. 

 

Taking Possia with food and drink 

You can take Possia with or without food. 

 

Pregnancy and breast-feeding 

It is not recommended to use Possia if you are pregnant or may become pregnant. Women should use 

appropriate contraceptive measures to avoid pregnancy while taking this medicine. 

Talk to your doctor before taking Possia if you are breast-feeding. Your doctor will discuss with you 

the benefits and risks of taking Possia during this time. 

 
Ask your doctor or pharmacist for advice before taking any medicine, if you are pregnant or breast-

feeding. 

 

Driving and using machines 
Possia is not likely to affect your ability to drive or use machines. 

 

 

3. How to take Possia 

 

Always take this medicine exactly as your doctor has told you.  Check with your doctor or pharmacist 

if you are not sure. 
 

How much to take 

 The starting dose is two tablets at the same time (loading dose of 180 mg). This dose will 
usually be given to you in the hospital. 

 After this starting dose, the usual dose is one tablet of 90 mg twice a day for up to 12 months 
unless your doctor tells you differently. Take Possia around the same time everyday (for 

example, one tablet in the morning and one in the evening). 

 

Your doctor will usually also tell you to take acetylsalicylic acid. This is a substance present in many 

medicines used to prevent blood clotting. Your doctor will tell you how much to take (usually between 

75-150 mg daily). 

 

How to take Possia 

 You can take the tablet with or without food. 

 You can check when you last took a tablet of Possia by looking on the blister. There is a sun 

(for the morning) and a moon (for the evening). This will tell you whether you have taken the 

dose. 
 

If you take more Possia than you should 

If you take more Possia than you should, talk to a doctor or go to hospital straight away. Take the 

medicine pack with you. You may be at increased risk of bleeding. 

 

If you forget to take Possia 

 If you forget to take a dose, just take your next dose as normal.  

 Do not take a double dose (two doses at the same time) to make up for the forgotten dose. 
 

If you stop taking Possia 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



32 

Do not stop taking Possia without talking to your doctor. Take Possia on a regular basis and for as 

long as your doctor keeps prescribing it. If you stop taking Possia, it may increase your chances of 

having another heart attack or stroke or dying from a disease related to your heart or blood vessels. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 

4.  Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. The 

following side effects may happen with this medicine: 

 

The frequency of possible side effects listed below is defined using the following convention: 

common (affects 1 to 10 users in 100); uncommon (affects 1 to 10 users in 1,000); rare (affects 1 to 10 

users in 10,000). 
 

See a doctor straight away if you notice any of the following – you may need urgent medical 

treatment: 

 Signs of a stroke such as: 

- sudden numbness or weakness of your arm, leg or face, especially if only on one side of the 

body 

- sudden confusion, difficulty speaking or understanding others 

- sudden difficulty in walking or loss of balance or co-ordination 

- suddenly feeling dizzy or sudden severe headache with no known cause 

These are signs of a kind of stroke caused by bleeding into the brain. This is uncommon. 
 

 Bleeding – some bleeding is common. However, severe bleeding is uncommon, but can be life 

threatening. Bleeding of many different kinds can be increased, for example: 

- nosebleed (common) 

- blood in your urine (uncommon) 

- black stools or blood in your stools (common) 

- blood in your eye (uncommon) 

- coughing up or bringing up blood (uncommon) 

- vaginal bleeding that is heavier, or happens at different times, to your normal period 

(menstrual) bleeding (uncommon) 

- bleeding after surgery or from cuts and wounds that is more than normal (common) 

- bleeding from your stomach lining (ulcer) (uncommon). 

- bleeding gums (uncommon) 

- blood in your ear (rare) 

- internal bleeding (rare) 

- bleeding into joints causing painful swelling (rare) 
 

Discuss with your doctor if you notice any of the following: 

 Feeling short of breath - this is common. It might be due to your heart disease or another 

cause, or it might be a side effect of Possia. If your feeling of shortness of breath gets worse or 

lasts a long time, tell your doctor. Your doctor will decide if it needs treatment or further 

investigations. 
 

Other possible side effects 

 

Common (affects 1 to 10 users in 100) 

 Bruising 
 

Uncommon (affects 1 to 10 users in 1,000) 

 Allergic reaction – a rash, itching, or a swollen face or swollen lips/tongue may be signs of an 

allergic reaction (see section 2: What you need to know before you take Possia). 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



33 

 Headache 

 Feeling dizzy or like the room is spinning 

 Abdominal pain 

 Diarrhoea or indigestion 

 Feeling or being sick 

 Rash 

 Itching 

 Inflamed stomach (gastritis) 
 

Rare (affects 1 to 10 users in 10,000) 

 Constipation 

 A tingling feeling 

 Confusion 
 

If you get any side effects, talk to your doctor or pharmacist, but do not stop taking Possia until you 

have spoken to them. This includes any possible side effects not listed in this leaflet. 

 

 

5. How to store Possia 
 

Keep this medicine out of the reach and sight of children. 

Do not use this medicine after the expiry date, which is stated on the blister and carton after EXP. The 

expiry date refers to the last day of that month. 

Do not throw away any medicinesvia wastewater or household waste. Ask your pharmacist how to  

throw away medicines you no longer use . These measures will help to protect the environment. 

 

 

6. Contents of the pack and other information 
 

What Possia contains  

 The active substance is ticagrelor. Each film-coated tablet contains 90 mg of ticagrelor. 
 

 The other ingredients are: 
Tablet core: mannitol (E421), dibasic calcium phosphate, sodium starch glycolate, 

hydroxypropyl-cellulose (E463), magnesium stearate (E470b) 

 

Tablet film coating: hypromellose (E464), titanium dioxide (E171), talc, 

polyethylene-glycol 400, and ferric oxide yellow (E172). 

 

What Possia looks like and contents of the pack 
Film-coated tablet (tablet): The tablets are round, biconvex, yellow, film-coated marked with a “90” 

above “T” on one side. 

 

Possia is available in: 

 standard blisters (with sun/moon symbols) in cartons of 60 and 180 tablets 

 calendar blisters (with sun/moon symbols) in cartons of 14, 56 and 168 tablets  

 perforated blisters in a carton of 100x1 tablets  
Not all pack sizes may be marketed. 

 

Marketing Authorisation Holder and Manufacturer 

 

Marketing Authorisation Holder: 

AstraZeneca AB 

S-151 85 

Södertälje 

Sweden 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



34 

 

Manufacturer: 

AstraZeneca AB 

Gärtunavägen 

SE-151 85 

Södertälje 

Sweden 

 

Manufacturer: 

AstraZeneca UK Limited 

Silk Road Business Park 

Macclesfield, Cheshire, SK10 2NA 

United Kingdom 

 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

NV AstraZeneca SA  

Tel: +32 2 370 48 11 

Luxembourg/Luxemburg 

NV AstraZeneca SA 

Tél/Tel: + 32 2 370 48 11 

 

България 

AstraZeneca България ЕООД 

Teл.: +359 2 971 25 33 

 

Magyarország 

AstraZeneca kft 

Tel.: + 36 1 883 6500 

Česká republika 

AstraZeneca Czech Republic s.r.o 

Tel: +420 222 807 111 

 

Malta 

Associated Drug Co. Ltd 
Tel: + 356 2277 8000 

 

Danmark 

AstraZeneca A/S 
Tlf: +45 43 66 64 62  

 

Nederland 

AstraZeneca BV 

Tel: +31 79 363 2222 

Deutschland 

AstraZeneca GmbH 

Tel: + 49 41 03 7080 

Norge 

AstraZeneca AS 

Tlf: + 47 21 00 64 00 

Eesti 

AstraZeneca  

Tel: +372 6549 600 

 

Österreich 

AstraZeneca Österreich GmbH 

Tel: +43 1 711 31 0 

Ελλάδα 

AstraZeneca A.E. 

Τηλ: + 30 2 106871500 

 

Polska 

AstraZeneca Pharma Poland Sp. z o.o. 

Tel.: + 48 22 874 35 00 

España 

Laboratorios Almirall, S.A. 

Tel: + 34 93 31 28 748 

Portugal 

Medinfar Produtos Farmacêuticos, S.A. 

Tel: + 351 21 499 74 00 

 

France 

AstraZeneca 

Tél: + 33 1 41 29 40 00 

România 

AstraZeneca Pharma SRL 

Tel: + 40 21 317 60 41 

Ireland 

AstraZeneca Pharmaceuticals (Ireland) Ltd 

Tel: + 353 1609 7100 

Slovenija 

AstraZeneca UK Limited 

Tel: + 386 1 51 35 600 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d



35 

 

Ísland 

Vistor hf 

Sími: + 354 535 7000 

 

Slovenská republika 

AstraZeneca AB o.z. 

Tel: + 421 2 5737 7777 

Italia 

AstraZeneca S.p.A. 

Tel: + 39 02 98011 

 

Suomi/Finland 

AstraZeneca Oy 

Puh/Tel: + 358 10 23 010 

Κύπρος 

Αλέκτωρ Φαρµακευτική Λτδ 
Τηλ: +357 22490305 

 

Sverige 

AstraZeneca AB 

Tel: +46 8 553 26 000 

Latvija 

SIA AstraZeneca Latvija 

Tel: + 371 67377100 

 

United Kingdom 

AstraZeneca UK Ltd 

Tel: + 44 1582 836 836 

Lietuva 

UAB AstraZeneca 

Tel: +370 5 2660550 

 

 

 

 

This leaflet was last  revised in  
 

Other sources of information 
 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu. 

 

Me
dic

ina
l p

ro
du

ct 
no

 lo
ng

er
 au

th
or

ise
d

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	19A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET