Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Summary of the safety profile
The safety profile of ticagrelor has been evaluated in two large phase 3 outcome trails (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 60mg with ASA vs. 8.5% for ASA therapy alone). The most commonly reported adverse reactions in patients treated with ticagrelor were bleeding and dyspnoea (see section 4.4)

Tabulated list of adverse reactions
The following adverse reactions have been identified following studies or have been reported in post-marketing experience with ticagrelor (Table 1).

Adverse reactions are listed by MedDRA System Organ Class (SOC). Within each SOC the adverse reactions are ranked by frequency category. Frequency categories are defined according to the following conventions: Very common (≥1/10), Common (≥1/100 to 1/10), Uncommon (≥1/1,000 to 1/100), Rare (≥1/10,000 to 1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available date).

Table 1     Adverse reactions by frequency and System Organ Class
(SOC)
SOC
Very common         Common             Uncommon          Not known
Neoplasms benign,                                                    Tumour malignant and
Bleedingsa
Unspecified (including cysts and polyps)
Blood and lymphatic           Blood disorder                                           Thrombotic system
Bleedingsb                                               Thrombocytopeni disorders c
Purpurac

Table 1    Adverse reactions by frequency and System Organ Class
(SOC)
SOC
Very common      Common           Uncommon         Not known
Immune system disorders                                        Hypersensitivity including angioedema c
Metabolism and nutrition     Hyperuricaemiad Gout / Gouty disorders                                    Arthritis
Psychiatric disorders                                          Confusion Nervous system disorders                      Dizziness,       Intracranial Syncope          haemorrhagem
Headache

Eye disorders                                                  Eye haemorrhagee
Ear and labyrinth                             Vertigo          Ear disorders                                                      haemorrhage Cardiac                                                                          Bradyarrhythmia, disorders                                                                        AV blockc Vascular disorders                            Hypotension
Respiratory, thoracic and    Dyspnoea         Respiratory mediastinal disorders system bleedingsf
Gastrointestinal disorders                    Gastrointestinal Retroperitoneal haemorrhageg     haemorrhage
Diarrhoea,
Nausea,Dyspe psia,
Constipation
Skin and subcutaneous                         Subcutaneous tissue disorders                              or dermal bleedingh,
Rash, Pruritus
Musculoskeletal                                                Muscular connective tissue and bleedingsi bone



Renal and urinary                             Urinary tract disorders                                     bleedingj
Reproductive system and                                        Reproductive breast disorders                                               system bleedingk
Investigations                                Blood creatinine increasedd



Table 1      Adverse reactions by frequency and System Organ Class
(SOC)
SOC
Very common          Common               Uncommon             Not known Injury, poisoning and                                Post procedural complications                             procedural haemorrhage,
Traumatic bleedingsl a  e.g. bleeding from bladder cancer, gastric cancer, colon cancer b  e.g. increased tendency to bruise, spontaneous haematoma, haemorrhagic diathesis c Identified in post-marketing experience d Frequencies derived from lab observations (Uric acid increases to >upper limit of normal from  baseline below or within reference range. Creatinine increases of >50% from baseline.) and not crude adverse event report frequency.
e e.g. conjunctival, retinal, intraocular bleeding f e.g. epistaxis, haemoptysis g e.g. gingival bleeding, rectal haemorrhage, gastric ulcer haemorrhage h e.g. ecchymosis, skin haemorrhage, petechiae i e.g. haemarthrosis, muscle haemorrhage j e.g. haematuria, cystitis haemorrhagic k e.g. vaginal haemorrhage, haematospermia, postmenopausal haemorrhage l e.g. contusion, traumatic haematoma, traumatic haemorrhage m i.e. spontaneous, procedure related or traumatic intracranial haemorrhage 


Description of selected adverse reactions

Bleeding
Bleeding findings in PLATO
Overall outcome of bleeding rates in the PLATO study are shown in Table 2.
Table 2 –Analysis of overall bleeding events Kaplan-Meier estimates at 12 months (PLATO)
Ticagrelor      Clopidogrel
90 mg
N=9186      p-value* twice daily
N=9235
PLATO Total Major                            11.6            11.2        0.4336 PLATO Major Fatal/Life-                       5.8             5.8        0.6988 Threatening
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 +                  5.9             4.3       0.0001 Minor
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.
*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
ASA alone daily +
N=6996
ASA N=6958

Safety Endpoints                              Hazard Ratio
KM%                               KM %              p-value
(95% CI)
TIMI-defined bleeding categories
2.3               2.32
1.1            <0.0001
TIMI Major                                        (1.68,3.21)
1.00
Fatal                         0.3                                 0.3            1.0000 (0.44, 2.27)



ICH                                            1.33
0.6                                  0.5             0.3130
(0.77, 2.31)
3.61
1.6                                  0.5            <0.0001
Other TIMI Major                           (2.31, 5.65)

2.54
3.4                                  1.4            <0.0001
TIMI Major or Minor                               (1.93, 3.35)
TIMI Major or Minor or                                2.64
Requiring medical attention         16.6                                 7.0            <0.0001 (2.35, 2.97)
PLATO-defined bleeding categories
PLATO Major                                           2.57
3.5                                          1.4             <0.0001
(1.95,3.37)
Fatal/Life-threatening                           2.38
2.4                                 1.1             <0.0001
(1.73,3.26)
Other PLATO Major                                3.37
1.1                                 0.3             <0.0001
(1.95,5.83)
PLATO Major or Minor
15.2           2.71                6.2             <0.0001
(2.40,3.08)
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/L decrease 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 section 4.4).

About 30% of episodes resolved within 7 days. PLATO included patients with baseline congestive heart failure, COPD, or asthma; these patients, and the elderly, were more likely to report dyspnoea. For 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.


Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il