Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile

Safety in patients with acute coronary syndrome undergoing PCI was evaluated in one clopidogrel- controlled study (TRITON) in which 6741 patients were treated with prasugrel (60 mg loading dose and 10 mg once daily maintenance dose) for a median of 14.5 months (5802 patients were treated for over 6 months, 4136 patients were treated for more than 1 year). The rate of study drug discontinuation due to adverse events was 7.2% for prasugrel and 6.3% for clopidogrel. Of these, bleeding was the most common adverse reaction for both drugs leading to study drug discontinuation (2.5% for prasugrel and 1.4% for clopidogrel).

Bleeding

Non-Coronary Artery Bypass Graft (CABG) related bleeding
In TRITON, the frequency of patients experiencing a non-CABG related bleeding event is shown in Table 1. The incidence of Non-CABG-related TIMI major bleeding, including life-threatening and fatal, as well as TIMI minor bleeding, was statistically significantly higher in subjects treated with prasugrel compared to clopidogrel in the UA/NSTEMI and All ACS populations. No significant difference was seen in the STEMI population. The most common site of spontaneous bleeding was the gastrointestinal tract (1.7% rate with prasugrel and 1.3% rate with clopidogrel); the most frequent site of provoked bleeding was the arterial puncture site (1.3% rate with prasugrel and 1.2% with clopidogrel).

Table 1: Incidence of Non-CABG related bleedinga (% Patients)



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Event                                All ACS                         UA/NSTEMI                        STEMI Prasugrelb Clopidogrelb          Prasugrelb Clopidogrelb        Prasugrelb Clopidogrelb +ASA          +ASA               +ASA         +ASA              +ASA         +ASA (N=6741)      (N=6716)           (N=5001)     (N=4980)          (N=1740)     (N=1736) TIMI major                      2.2           1.7                2.2          1.6               2.2          2.0 bleedingc
Life-threateningd            1.3              0.8                1.3            0.8            1.2              1.0 Fatal                       0.3              0.1                0.3            0.1            0.4              0.1 Symptomatic                 0.3              0.3                0.3            0.3            0.2              0.2 ICHe
Requiring                   0.3              0.1                0.3            0.1            0.3              0.2 inotropes
Requiring                  0.3              0.3                0.3            0.3            0.1              0.2 surgical intervention
Requiring                  0.7              0.5                0.6            0.3            0.8              0.8 transfusion (≥4 units)
TIMI minor bleeding            2.4              1.9                2.3            1.6            2.7              2.6 f
 a Centrally adjudicated events defined by the Thrombolysis in Myocardial Infarction (TIMI) Study Group criteria.
b Other standard therapies were used as appropriate.
c Any intracranial haemorrhage or any clinically overt bleeding associated with a fall in haemoglobin ≥5 g/dL.
d Life-threatening bleeding is a subset of TIMI major bleeding and includes the types indented below. Patients may be counted in more than one row.
e ICH=intracranial haemorrhage.
f Clinically overt bleeding associated with a fall in haemoglobin of ≥3 g/dL but <5 g/dL.

Patients ≥ 75 years old
Non-CABG-related TIMI major or minor bleeding rates:

Age                     Prasugrel 10 mg                 Clopidogrel 75 mg ≥75 years (N=1785)               9.0% (1.0% fatal)               6.9% (0.1% fatal) <75 years (N=11672)              3.8% (0.2% fatal)               2.9% (0.1% fatal) <75 years (N=7180)**             2.0% (0.1% fatal) a              1.3% (0.1% fatal) Prasugrel 5 mg                Clopidogrel 75 mg
≥75 years (N=2060) **             2.6% (0.3% fatal)               3.0% (0.5% fatal) *TRITON study in ACS patients undergoing PCI
**TRILOGY-ACS study in patients not undergoing PCI (see 5.1): a
10 mg prasugrel; 5 mg prasugrel if <60 kg

Patients < 60 kg
Non-CABG-related TIMI major or minor bleeding rates:

Weight                   Prasugrel 10 mg                 Clopidogrel 75 mg <60 kg (N=664)*                  10.1% (0% fatal)                6.5% (0.3% fatal) ≥60 kg (N=12672)*                4.2% (0.3% fatal)               3.3% (0.1% fatal) ≥60 kg (N=7845)**                2.2% (0.2% fatal) a              1.6% (0.2% fatal) Prasugrel 5 mg                 Clopidogrel 75 mg
<60kg (N=1391)**                 1.4% (0.1% fatal)                2.2% (0.3% fatal) *TRITON study in ACS patients undergoing PCI
**TRILOGY-ACS study in patients not undergoing PCI (see 5.1):


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a
10 mg prasugrel; 5 mg prasugrel if ≥75 years of age
Patients ≥60 kg and age <75 years
In patients ≥60 kg and age <75 years, non-CABG-related TIMI major or minor bleeding rates were 3.6% for prasugrel and 2.8% for clopidogrel; rates for fatal bleeding were 0.2% for prasugrel and 0.1% for clopidogrel.

CABG-related bleeding
In the phase 3 clinical trial, 437 patients underwent CABG during the course of the study. Of those patients, the rate of CABG-related TIMI major or minor bleeding was 14.1% for the prasugrel group and 4.5% in the clopidogrel group. The higher risk for bleeding events in subjects treated with prasugrel persisted up to 7 days from the most recent dose of study drug. For patients who received their thienopyridine within 3 days prior to CABG, the frequencies of TIMI major or minor bleeding were 26.7% (12 of 45 patients) in the prasugrel group, compared with 5.0% (3 of 60 patients) in the clopidogrel group. For patients who received their last dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies decreased to 11.3% (9 of 80 patients) in the prasugrel group and 3.4% (3 of 89 patients) in the clopidogrel group. Beyond 7 days after drug discontinuation, the observed rates of CABG-related bleeding were similar between treatment groups (see section 4.4).

Bleeding Risk Associated with Timing of Loading Dose in NSTEMI
In a clinical study of NSTEMI patients (the ACCOAST study), where patients were scheduled to undergo coronary angiography within 2 to 48 hours after randomization, patients given a 30 mg loading dose on average 4 hours prior to coronary angiography followed by a 30 mg loading dose at the time of PCI had an increased risk of non-CABG peri-procedural bleeding and no additional benefit compared to patients receiving a 60 mg loading dose at the time of PCI (see sections 4.2 and 4.4).
Non-CABG- related TIMI bleeding rates through 7 days for patients were as follows: 
Prasugrel Prior to           Prasugrel At
Adverse Reaction                                                 Coronary                 time of PCIa Angiographya
(N=2037)                   (N=1996)
%                          %

TIMI Major bleedingb                                                  1.3                      0.5 c                                                  0.8                      0.2 Life-threatening
Fatal                                                            0.1                      0.0 Symptomatic ICHd                                                 0.0                      0.0 Requiring inotropes                                              0.3                      0.2 Requiring surgical intervention                                  0.4                      0.1 Requiring transfusion (≥4 units)                                 0.3                      0.1 TIMI Minor bleedinge                                                  1.7                      0.6 a
Other standard therapies were used as appropriate. The clinical study protocol provided for all patients to receive aspirin and a daily maintenance dose of prasugrel.
bAny intracranial haemorrhage or any clinically overt bleeding associated with a fall in haemoglobin ≥5 g/dL.
c
Life-threatening is a subset of TIMI Major bleeding and includes the types indented below. Patients may be counted in more than one row.
dICH=intracranial haemorrhage.
e
Clinically overt bleeding associated with a fall in haemoglobin of ≥3 g/dL but <5 g/dL.

Tabulated summary of adverse reactions



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Table 2 summarises haemorrhagic and non-haemorrhagic adverse reactions in TRITON, or that were spontaneously reported, classified by frequency and system organ class. Frequencies are defined as follows:
Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 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 2: Haemorrhagic and Non-haemorrhagic adverse reactions

System Organ           Common                   Uncommon                   Rare                Not Known Class
Blood and              Anaemia                                             Thrombocytopaenia   Thrombotic Lymphatic System                                                                               thrombocytopaenic disorders                                                                                      purpura (TTP) -see section 4.4
Immune system                                   Hypersensitivity disorders                                       including angioedema
Eye disorders                                   Eye haemorrhage
Vascular               Haematoma
Disorders
Respiratory,           Epistaxis                Haemoptysis thoracic and mediastinal disorders
Gastrointestinal       Gastrointestinal         Retroperitoneal disorders              haemorrhage              haemorrhage
Rectal haemorrhage
Haematochezia
Gingival bleeding
Skin and               Rash subcutaneous           Ecchymosis tissue disorders
Renal and urinary      Haematuria disorders
General disorders      Vessel puncture site and administration     haematoma site conditions        Puncture site haemorrhage
Injury, poisoning      Contusion                Post-procedural            Subcutaneous and procedural                                  haemorrhage                haematoma complications

In patients with or without a history of TIA or stroke, the incidence of stroke in the phase 3 clinical trial was as follows (see section 4.4):

History of TIA or                Prasugrel                      Clopidogrel stroke
Yes (N=518)               6.5% (2.3% ICH*)                1.2% (0% ICH*) No (N=13090)              0.9% ( 0.2% ICH*)              1.0% (0.3% ICH*) * ICH=intracranial haemorrhage.

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.


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Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.go v.il