ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Angiox 250 mg powder for concentrate for solution for injection or infusion.
2.
Each vial contains 250 mg bivalirudin.
After reconstitution 1 ml contains 50 mg bivalirudin.
After dilution 1 ml contains 5 mg bivalirudin.
For a full list of excipients see section 6.1.
3.
Powder for concentrate for solution for injection or infusion.
White to off-white lyophilised powder.
4.
Angiox is indicated as an anticoagulant in adult patients undergoing percutaneous coronary
intervention (PCI), including patients with ST-segment elevation myocardial infarction (STEMI)
undergoing primary PCI.
Angiox is also indicated for the treatment of adult patients with unstable angina/non-ST segment
elevation myocardial infarction (UA/NSTEMI) planned for urgent or early intervention.
Angiox should be administered with aspirin and clopidogrel.
Angiox should be administered by a physician experienced in either acute coronary care or in coronary
intervention procedures.
Posology
Patients undergoing PCI, including primary PCI
The recommended dose of Angiox for patients undergoing PCI is an intravenous bolus of 0.75 mg/kg
body weight followed immediately by an intravenous infusion at a rate of 1.75 mg/kg body
weight/hour for at least the duration of the procedure. The infusion may be continued for up to 4 hours
post-PCI as clinically warranted.
After cessation of the 1.75 mg/kg /h infusion, a reduced infusion
dose of 0.25 mg/kg/h may be continued for 4 – 12 hours as clinically necessary.
Patients should be carefully monitored following primary PCI for signs and symptoms consistent with
myocardial ischaemia.
2
Patients with unstable angina/non-ST segment elevated myocardial infarction (UA/NSTEMI)
The recommended starting dose of Angiox for patients with ACS is an intravenous bolus of 0.1 mg/kg
followed by an infusion of 0.25 mg/kg/h. Patients who are to be medically managed may continue the
infusion of 0.25 mg/kg/h for up to 72 hours.
If the patient proceeds to PCI, an additional bolus of 0.5 mg/kg of bivalirudin should be administered
before the procedure and the infusion increased to 1.75 mg/kg/h for the duration of the procedure.
Following PCI, the reduced infusion dose of 0.25 mg/kg/h may be resumed for 4 to 12 hours as
clinically necessary.
For patients who proceed to coronary artery bypass graft (CABG) surgery off pump, the intravenous
(IV) infusion of bivalirudin should be continued until the time of surgery. Just prior to surgery, a 0.5
mg/kg bolus dose should be administered followed by a 1.75 mg/kg/h infusion for the duration of the
surgery.
For patients who proceed to CABG surgery on pump, the IV infusion of bivalirudin should be
continued until 1 hour prior to surgery after which the infusion should be discontinued and the patient
treated with unfractionated heparin (UFH).
The safety and efficacy of a bolus only dose of Angiox has not been evaluated and is not
recommended even if a short PCI procedure is planned.
The activated clotting time (ACT) may be used to assess bivalirudin activity.
In order to reduce the potential for low ACT values, the reconstituted and diluted product should be
thoroughly mixed prior to administration and the bolus dose administered by a rapid intravenous push.
ACT values 5 minutes after bivalirudin bolus average 365 +/- 100 seconds. If the 5-minute ACT is less
than 225 seconds, a second bolus dose of 0.3 mg/kg should be administered.
Once the ACT value is greater than 225 seconds, no further monitoring is required provided the 1.75
mg/kg infusion dose is properly administered.
The arterial sheath can be removed 2 hours after discontinuation of the bivalirudin infusion without
further ACT monitoring.
Renal insufficiency
Angiox is contraindicated in patients with severe renal insufficiency (GFR<30 ml/min) and also in
dialysis-dependent patients (see section 4.3).
In patients with mild or moderate renal insufficiency, the ACS dose (0.1 mg/kg bolus/0.25 mg/kg/h
infusion) should not be adjusted.
Patients with moderate renal impairment (GFR 30-59 ml/min) undergoing PCI (whether being treated
with bivalirudin for ACS or not) should receive a lower infusion rate of 1.4 mg/kg/h. The bolus dose
should not be changed from the posology described under ACS or PCI above.
During PCI, monitoring of clotting time such as the ACT is recommended in patients with renal
insufficiency.
The ACT should be checked at 5 minutes post bolus dose. If the ACT is less than 225 seconds, a
second bolus dose of 0.3 mg/kg should be administered and the ACT re-checked 5 minutes after the
administration of the second bolus dose.
3
Hepatic impairment
No dose adjustment is needed. Pharmacokinetic studies indicate that hepatic metabolism of bivalirudin
is limited, therefore the safety and efficacy of bivalirudin have not been specifically studied in patients
with hepatic impairment.
Elderly population
Caution should be exercised in the elderly due to age-related decrease in renal function.
Paediatric patients
There is no relevant indication for use of Angiox in children less than 18 years old.
Use with other anticoagulant therapy
In STEMI patients undergoing primary PCI, standard pre-hospital adjunctive therapy should include
clopidogrel and may include the early administration of UFH
(See section 5.1).
Patients can be started on Angiox 30 minutes after discontinuation of unfractionated heparin
given intravenously, or 8 hours after discontinuation of low molecular weight heparin given
subcutaneously.
Angiox can be used in conjunction with a GP IIb/IIIa inhibitor. Refer to section 5.1 for further
information regarding the use of bivalirudin with or without a GP IIb/IIIa inhibitor.
Method of administration
Angiox is intended for intravenous (IV) use.
Angiox should be initially reconstituted to give a solution of 50 mg/ml bivalirudin. Reconstituted
material should then be further diluted in a total volume of 50 ml to give a solution of 5 mg/ml
bivalirudin.
Reconstituted and diluted product should be thoroughly mixed prior to administration.
Refer to section 6.6 for full instructions regarding the method of administration.
Angiox is administered as a weight based regimen consisting of an initial bolus (by rapid IV push)
followed by an IV infusion.
Angiox is contraindicated in patients with:
•
a known hypersensitivity to the active substance or to any of the excipients, or to hirudins
•
active bleeding or increased risk of bleeding because of haemostasis disorders and/or
irreversible coagulation disorders
•
severe uncontrolled hypertension
•
subacute bacterial endocarditis
•
severe renal impairment (GFR<30 ml/min) and in dialysis-dependent patients.
Angiox
is not intended for intramuscular use. Do not administer intramuscularly.
Haemorrhage
Patients must be observed carefully for symptoms and signs of bleeding during treatment particularly
if bivalirudin is combined with another anticoagulant (see section 4.5). Although most bleeding
associated with bivalirudin occurs at the site of arterial puncture in patients undergoing PCI,
haemorrhage can occur at any site during therapy. Unexplained decreases in haematocrit, haemoglobin
4
or blood pressure may indicate haemorrhage. Treatment should be stopped if bleeding is observed or
suspected.
There is no known antidote to bivalirudin but its effect wears off quickly (T
½
is 35 to 40 minutes).
Co-administration with platelet inhibitors or anti-coagulants
Combined use of anti-coagulant medicines can be expected to increase the risk of bleeding (see
section 4.5). When bivalirudin is combined with a platelet inhibitor or an anti-coagulant medicine,
clinical and biological parameters of haemostasis should be regularly monitored.
In patients taking warfarin who are treated with bivalirudin, International Normalised Ratio (INR)
monitoring should be considered to ensure that it returns to pre-treatment levels following
discontinuation of bivalirudin treatment.
Hypersensitivity
Allergic type hypersensitivity reactions were reported uncommonly (≥1/1,000 to ≤1/100) in clinical
trials. Necessary preparations should be made to deal with this. Patients should be informed of the
early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of chest,
wheezing, hypotension and anaphylaxis. In the case of shock, the current medical standards for shock
treatment should be applied. Anaphylaxis, including anaphylactic shock with fatal outcome has been
reported very rarely (≤1/10,000) in post-marketing experience (see section 4.8).
Treatment-emergent positive bivalirudin antibodies are rare and have not been associated with clinical
evidence of allergic or anaphylactic reactions. Caution should be exercised in patients previously
treated with lepirudin who had developed lepirudin antibodies.
Acute stent thrombosis
Acute stent thrombosis (<24 hours) has been observed in patients with STEMI undergoing primary
PCI and has been managed by Target Vessel Revascularisation (TVR) (see sections 4.8 and 5.1).
Patients should remain for at least 24 hours in a facility capable of managing ischaemic complications
and should be carefully monitored following primary PCI for signs and symptoms consistent with
myocardial ischaemia.
Brachytherapy
Intra-procedural thrombus formation has been observed during gamma brachytherapy procedures with
Angiox.
Angiox should be used with caution during beta brachytherapy procedures.
Interaction studies have been conducted with platelet inhibitors, including acetylsalicylic acid,
ticlopidine, clopidogrel, abciximab, eptifibatide, or tirofiban. The results do not suggest
pharmacodynamic interactions with these medicinal products.
From the knowledge of their mechanism of action, combined use of anti-coagulant medicinal products
(heparin, warfarin, thrombolytics or antiplatelet agents) can be expected to increase the risk of
bleeding.
In any case, when bivalirudin is combined with a platelet inhibitor or an anticoagulant medicine,
clinical and biological parameters of haemostasis should be regularly monitored.
5
Pregnancy
There are no or limited data from the use of bivalirudin in pregnant women. Animal studies are
insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition or post-
natal development (see section 5.3).
Angiox should not be used during pregnancy unless the clinical condition of the woman requires
treatment with bivalirudin.
Breastfeeding
It is unknown whether bivalirudin is excreted in human milk. Angiox should be administered with
caution in breast-feeding mothers.
No studies on the effects on the ability to drive and use machines have been performed.
In all clinical studies bleeding data were collected separately from adverse drug reactions and are
summarised in Table 8 together with the bleeding definitions used for each study.
The HORIZONS Trial (Patients with STEMI undergoing primary PCI)
The following adverse reaction data are based on a clinical study of bivalirudin in patients with
STEMI undergoing primary PCI; 1,800 patients were randomised to bivalirudin alone, 1,802 were
randomised to heparin plus GP IIb/IIIa inhibitor. Serious adverse reactions were reported more
frequently in the heparin plus GP IIb/IIIa group than the bivalirudin treated group.
A total of 55.1% of patients receiving bivalirudin experienced at least one adverse event and 8.7%
experienced an adverse drug reaction. Adverse drug reactions for bivalirudin are listed by system
organ class in Table 1.The incidence of stent thrombosis within the first 24 hours was 1.5% in patients
receiving bivalirudin versus 0.3% in patients receiving UFH plus GP IIb/IIIa inhibitor (p=0.0002).
Two deaths occurred after acute stent thrombosis, 1 in each arm of the study. The incidence of stent
thrombosis between 24 hours and 30 days was 1. 2% in patients receiving bivalirudin versus 1.9% in
patients receiving UFH plus GP IIb/IIIa inhibitor (p=0.1553). A total of 17 deaths occurred after
subacute stent thrombosis, 3 in the bivalirudin arm and 14 in the UFH plus GP IIb/IIIa arm. There was
no statistically significant difference in the rates of stent thrombosis between treatment arms at 30
days (p=0.3257) and 1 year (p=0.7754).
1/100 and <1/10).
The incidence of major and minor bleeding was significantly less in patients treated with bivalirudin
versus patients treated with heparin plus a GP IIb/IIIa inhibitor. The incidence of major bleeding is
shown in Table 8. Major bleeding occurred most frequently at the sheath puncture site. The most
frequent event was a haematoma <5 cm at puncture site.
≥
In the HORIZONS study, thrombocytopenia was reported in 26 (1. 6%) of bivalirudin-treated patients
and in 67 (3.9%) of patients treated with heparin plus a GP IIb/IIIa inhibitor. All of these bivalirudin-
treated patients received concomitant aspirin, all but 1 received clopidogrel and 15 also received a GP
IIb/IIIa inhibitor.
6
Platelets, bleeding and clotting
In the HORIZONS study both major and minor bleeding occurred commonly (
Table 1. HORIZONS trial; adverse drug reaction data
System organ
class
Common
(≥1/100 to
<1/10)
Uncommon
(≥1/1,000 to ≤1/100)
Rare
≥1/10,000 to ≤1/1,000
Blood and the
lymphatic system
disorders
Anaemia,
Thrombocytopenia
Immune system
disorders
Hypersensitivity
including
anaphylactic reaction
and shock, including
reports with fatal
outcome
Nervous system
disorders
Intracranial
haemorrhage
Headache
Cardiac disorders
Angina pectoris,
Coronary artery
thrombosis
Vascular disorders Major
haemorrhage
at any site,
including
reports with
fatal
outcome,
Minor
haemorrhage
Haematoma,
Hypotension
Vascular pseudoaneurysm
Gastrointestinal
disorders
Retroperitoneal
haemorrhage,
Haematemesis,
Gastrointestinal
haemorrhage,
Melaena, Nausea
Oesophageal haemorrhage, Peritoneal
haemorrhage, Retroperitoneal
haematoma, Vomiting
Respiratory,
thoracic and
mediastinal
disorders
Haemoptysis,
Epistaxis, Pulmonary
haemorrhage
Skin and
subcutaneous tissue
disorders
Ecchymosis
Rash
Musculoskeletal
and connective
tissue disorders
Groin pain
Injury, poisoning
and procedural
complications
Coronary
stent
thrombosis
including
reports with
fatal
outcome,
Vessel
puncture site
haematoma,
Vessel
Reperfusion injury
(no or slow reflow),
Contusion
7
System organ
class
Common
(≥1/100 to
<1/10)
Uncommon
(≥1/1,000 to ≤1/100)
Rare
≥1/10,000 to ≤1/1,000
puncture site
haemorrhage
Renal and urinary
disorders
Haematuria
The ACUITY Trial (
Patients with unstable angina/non-ST segment elevated myocardial infarction
(UA/NSTEMI))
The following adverse reaction data are based on a clinical study of bivalirudin in 13,819 patients with
ACS; 4,612 were randomised to bivalirudin alone, 4,604 were randomised to bivalirudin plus GP
IIb/IIIa inhibitor and 4,603 were randomised to either unfractionated heparin or enoxaparin plus GP
IIb/IIIa inhibitor. Adverse reactions were more frequent in females and in patients more than 65 years
of age in both the bivalirudin and the heparin-treated comparator groups compared to male or younger
patients.
Approximately 23.3% of patients receiving bivalirudin experienced at least one adverse event and
2.1% experienced an adverse reaction. Adverse event reactions for bivalirudin are listed by system
organ class in Table 2.
Platelets, bleeding and clotting
In ACUITY, bleeding data were collected separately from adverse reactions.
ACUITY major bleeding was defined as any one of the following: intracranial, retroperitoneal,
intraocular, access site haemorrhage requiring radiological or surgical intervention, ≥5 cm diameter
haematoma at puncture site, reduction in haemoglobin concentration of ≥4 g/dl without an overt
source of bleeding, reduction in haemoglobin concentration of ≥3 g/dl with an overt source of
bleeding, re-operation for bleeding or use of any blood product transfusion. Minor bleeding
was
defined as any observed bleeding event that did not meet the criteria as major. Minor bleeding
occurred very commonly (
≥
1/10) and major bleeding occurred commonly (
≥
1/100 and <1/10).
Major bleeding rates are shown in Table 8 for the IIT population and Table 10 for the per protocol
population (patients receiving clopidogrel and aspirin). Both major and minor bleeds were
significantly less frequent with bivalirudin alone than the heparin plus GP IIb/IIIa inhibitor and
bivalirudin plus GP IIb/IIIa inhibitor groups. Similar reductions in bleeding were observed in patients
who were switched to bivalirudin from heparin-based therapies (N = 2,078).
Major bleeding occurred most frequently at the sheath puncture site. Other less frequently observed
bleeding sites with greater than 0.1% (uncommon) bleeding included “other” puncture site,
retroperitoneal, gastrointestinal, ear, nose or throat.
Thrombocytopenia was reported in 10 bivalirudin-treated patients participating in the ACUITY study
(0.1%). The majority of these patients received concomitant acetylsalicylic acid and clopidogrel, and 6
out of the 10 patients also received a GP IIb/IIIa inhibitor. Mortality among these patients was nil.
Table 2. ACUITY trial; adverse reaction data
System organ class
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
Blood and lymphatic
system disorders
INR increased,
Thrombocytopenia,
8
System organ class
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
Anaemia.
Immune system disorders
Hypersensitivity,
including
anaphylactic reaction
and shock, including
reports with fatal
outcome
Nervous system disorders
Headache
Intracranial
haemorrhage
Ear and labyrinth
disorders
Ear haemorrhage
Cardiac disorders
Bradycardia,
Pericardial
haemorrhage
Vascular disorders
Minor
haemorrhage
at any site
Major
haemorrhage
at any site
including
reports with
fatal
outcome,
Thrombosis
including
reports with
fatal
outcome
Hypotension,
Vascular
pseudoaneurysm
Respiratory, thoracic and
mediastinal disorders
Epistaxis
Pharyngeal
haemorrhage,
Haemoptysis
Gastrointestinal disorders
Gastrointestinal
haemorrhage,
Gingival
haemorrhage,
Nausea,
Retroperitoneal
haemorrhage,
Melaena,Vomiting
Haematemesis
Skin and subcutaneous
tissue disorders
Ecchymosis
Urticaria, Rash
Musculoskeletal and
connective tissue
disorders
Chest pain, Back
pain, Groin pain
Renal and urinary
disorders
Haematuria
General disorders and
administration site
conditions
Vessel
puncture site
haemorrhage,
Vessel
puncture site
haematoma
<5 cm
Vessel puncture site
haematoma >5 cm
Injection site
reactions
9
The REPLACE-2 Trial
(Patients undergoing PCI)
The following adverse reaction data is based on a clinical study of bivalirudin in 6,000 patients
undergoing PCI, half of whom were treated with bivalirudin (REPLACE-2). Adverse events were
more frequent in females and in patients more than 65 years of age in both the bivalirudin and the
heparin-treated comparator groups compared to male or younger patients.
Approximately 30% of patients receiving bivalirudin experienced at least one adverse event and 3%
experienced an adverse reaction. Adverse reactions for bivalirudin are listed by system organ class in
Table 3.
Platelets, bleeding and clotting
In REPLACE-2, bleeding data were collected separately from adverse events. Major bleeding rates for
the intent-to-treat trial population is shown in Table 8.
Major bleeding was defined as the occurrence of any of the following: intracranial haemorrhage,
retroperitoneal haemorrhage, blood loss leading to a transfusion of at least two units of whole blood or
packed red blood cells, or bleeding resulting in a haemoglobin drop of more than 3 g/dl, or a fall in
haemoglobin greater than 4 g/dl (or 12% of haematocrit) with no bleeding site identified. Minor
haemorrhage was defined as any observed bleeding event that did not meet the criteria for a major
haemorrhage. Minor bleeding occurred very commonly (
≥
1/10) and major bleeding occurred
commonly (
≥
1/100 and <1/10).
Both minor and major bleeds were significantly less frequent with bivalirudin than the heparin plus
GP IIb/IIIa inhibitor comparator group. Major bleeding occurred most frequently at the sheath
puncture site. Other less frequently observed bleeding sites with greater than 0.1% (uncommon)
bleeding included “other” puncture site, retroperitoneal, gastrointestinal, ear, nose or throat.
In REPLACE-2 thrombocytopenia occurred in 20 bivalirudin-treated patients (0.7%). The majority of
these patients received concomitant aspirin and clopidogrel, and 10 out of 20 patients also received a
GP IIb/IIIa inhibitor. Mortality among these patients was nil.
Table 3. REPLACE-2 trial; adverse reaction data
System organ
class
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
Blood and the
lymphatic
system
disorders
Thrombocytopenia,
anaemia
Immune system
disorders
Hypersensitivity,
including anaphylactic
reaction and shock,
including reports with
fatal outcome
Nervous system
disorders
Headache
Intracranial
haemorrhage
Ear and
labyrinth
disorders
Ear
haemorrhage
Cardiac
disorders
Angina pectoris,
Pericardial
haemorrhage,
Ventricular
10
System organ
class
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
tachycardia,
Bradycardia
Vascular
disorders
Minor haemorrhage
at any site
Major
haemorrhage at any
site, including
reports with fatal
outcome,
Thrombosis
including reports
with fatal outcome
Hypotension, Vascular
disorder, Vascular
anomaly
Respiratory,
thoracic and
mediastinal
disorders
Epistaxis, Pharyngeal
haemorrhage,
Dyspnoea,
Haemoptysis
Gastrointestinal
disorders
Nausea, Gingival
haemorrhage Vomiting,
Retroperitoneal
haemmorrhage,
Gastrointestinal
haemorrhage
Skin and
subcutaneous
tissue disorders
Rash, Urticaria
Musculoskeletal
and connective
tissue disorders
Back pain
Renal and
urinary
disorders
Haematuria
General
disorders and
administration
site conditions
Vessel puncture site
haemorrhage, Injection
site pain, Chest pain,
Injection site
haemorrhage.
Cases of overdose of up to 10 times the recommended dose have been reported in clinical trials. Single
bolus doses of bivalirudin up to 7.5 mg/kg have also been reported. Bleeding has been observed in
some reports of overdose.
In cases of overdose, treatment with bivalirudin should be immediately discontinued and the patient
monitored closely for signs of bleeding.
In the event of major bleeding, treatment with bivalirudin should be immediately discontinued. There
is no known antidote to bivalirudin, however, bivalirudin is haemo-dialysable.
11
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Direct thrombin inhibitors, ATC code: B01AE06.
Angiox contains bivalirudin, a direct and specific thrombin inhibitor that binds both to the catalytic
site and the anion-binding exosite of fluid-phase and clot-bound thrombin.
Thrombin plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin
monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-
linked framework that stabilises the thrombus. Thrombin also activates Factors V and VIII, promoting
further thrombin generation, and activates platelets, stimulating aggregation and granule release.
Bivalirudin inhibits each of these thrombin effects.
The binding of bivalirudin to thrombin, and therefore its activity, is reversible as thrombin slowly
cleaves the bivalirudin, Arg
3
-Pro
4
, bond, resulting in recovery of thrombin active site function. Thus,
bivalirudin initially acts as a complete non-competitive inhibitor of thrombin, but transitions over time
to become a competitive inhibitor enabling initially inhibited thrombin molecules to interact with other
clotting substrates and to coagulation if required.
In vitro
studies have indicated that bivalirudin inhibits both soluble (free) and clot-bound thrombin.
Bivalirudin remains active and is not neutralised by products of the platelet release reaction.
In vitro
studies have also shown that bivalirudin prolongs the activated partial thromboplastin time
(aPTT) thrombin time (TT) and pro-thrombin time (PT) of normal human plasma in a concentration-
dependent manner and that bivalirudin does not induce a platelet aggregation response against sera
from patients with a history of Heparin-Induced Thrombocytopenia/Thrombosis Syndrome
(HIT/HITTS).
In healthy volunteers and patients, bivalirudin exhibits dose- and concentration-dependent
anticoagulant activity as evidenced as prolongation of the ACT, aPTT, PT, INR and TT. Intravenous
administration of bivalirudin produces measurable anticoagulation within minutes.
The pharmacodynamic effects of bivalirudin may be assessed using measures of anticoagulation
including the ACT. The ACT value is positively correlated with the dose and plasma concentration of
bivalirudin administered. Data from 366 patients indicates that the ACT is unaffected by concomitant
treatment with a GP IIb/IIIa inhibitor.
In clinical studies bivalirudin has been shown to provide adequate anticoagulation during PCI
procedures.
The HORIZONS Trial
(Patients with STEMI undergoing primary PCI)
The HORIZONS trial was a prospective, dual arm, single blind, randomised, multi-centre trial to
establish the safety and efficacy of bivalirudin in patients with STEMI undergoing a primary PCI
strategy with stent implantation with either a slow release paclitaxal-eluding stent (TAXUS™) or an
otherwise identical uncoated bare metal stent (Express2™). A total of 3,602 patients were randomised
to receive either bivalirudin (1,800 patients) or unfractionated heparin plus a GP IIb/IIIa inhibitor
(1,802 patients). All patients received aspirin and clopidogrel with twice as many patients
(approximately 64%) receiving a 600mg loading dose of clopidogrel than a 300mg loading dose of
clopidogrel. Approximately 66% of patients were pre-treated with unfractionated heparin.
The dose of bivalirudin used in HORIZONS was the same as that used in the REPLACE-2 study (0.75
mg/kg bolus followed by a 1.75 mg/kg body weight/hour infusion). A total of 92.9% of patients
treated underwent primary PCI as their primary management strategy.
12
The analysis and results for the HORIZONS trial at 30 days for the overall (ITT) population is shown
in Table 4.Results at 1 year were consistent with results at 30 days.
Bleeding definitions and outcomes from the HORIZONS trial are shown in Table 8.
Table 4
.
HORIZONS 30-day study results (intent-to-treat population)
Endpoint
Bivalirudin
(%)
Unfractionated
heparin + GP
IIb/IIIa
inhibitor (%)
Relative Risk
[95% CI]
p-value*
N = 1,800
N = 1,802
30 day Composite
MACE
1
5.4
5.5
0.98
[0.75, 1.29]
0.8901
Major bleeding
2
5.1
8.8
0.58
[0.45, 0.74]
<0.0001
Ischaemic Components
All cause death
2.1
3.1
0.66
[0.44, 1.0]
0.0465
Reinfarction
1.9
1.8
1.06
[0.66, 1.72]
0.8003
Ischaemic target
vessel
revascularisation
2.5
1.9
1.29 [0.83,1.99]
0.2561
Stroke
0.8
0.7
1.17
[0.54, 2.52]
0.6917
*Superiority p-value.
1
Major Adverse Cardiac/Ischaemic Events (MACE) was defined as the occurrence of any
of the following; death, reinfarction, stroke or ischaemic target vessel revascularisation.
2
Major bleeding was
defined using the ACUITY bleeding scale.
ACUITY Trial
(Patients with unstable angina/non-ST segment elevated myocardial infarction
(UA/NSTEMI)
The ACUITY trial was a prospective, randomised open-label, trial of bivalirudin with or without GP
IIb/IIIa inhibitor (Arms B and C respectively) versus unfractionated heparin or enoxaparin with GP
IIb/IIIa inhibitor (Arm A) in 13,819 high risk ACS patients.
In Arms B and C of the ACUITY trial, the recommended dose of bivalirudin was an initial post-
randomisation IV bolus of 0.1 mg/kg followed by a continuous IV infusion of 0.25 mg/kg/h during
angiography or as clinically warranted.
For patients undergoing PCI, an additional IV bolus of 0.5 mg/kg bivalirudin was administered and the
rate of IV infusion increased to 1.75 mg/kg/h.
In Arm A of the ACUITY trial, UFH or enoxaparin was administered in accordance with the relevant
guidelines for the management of ACS in patients with UA and NSTEMI. Patients in Arms A and B
were also randomised to receive a GP IIb/IIIa inhibitor either upfront at the time of randomization
(prior to angiography) or at the time of PCI. A total of 356 (7.7%) of patients randomised to Arm C
also received a GP IIb/IIIa inhibitor.
13
High risk patient characteristics of the ACUITY population that mandated angiography within 72
hours were balanced across the three treatment arms. Approximately 77% of patients had recurrent
ischaemia, approximately 70% had dynamic ECG changes or elevated cardiac biomarkers,
approximately 28% had diabetes and approximately 99% of patients underwent angiography within 72
hours.
Following angiographic assessment, patients were triaged to either medical management (33%), PCI
(56%) or CABG (11%). Additional anti-platelet therapy utilised in the study included aspirin and
clopidogrel.
The primary analysis and results for ACUITY at 30-days and 1 year for the overall (ITT) population
and for the patients that received aspirin and clopidogrel as per protocol (pre-angiography or pre-PCI)
are shown in Tables 5 and 6.
Table 5. ACUITY trial; 30-day and 1-year risk differences for the composite ischaemic
endpoint and its components for the overall population (ITT)
Overall population (ITT)
Arm A
UFH/enox
+GP IIb/IIIa
inhibitor
(N=4,603)
%
Arm B
bival +GP
IIb/IIIa
inhibitor
(N=4,604)
%
B – A
Risk diff.
(95% CI)
Arm C
bival
alone
(N=4,612)
%
C – A
Risk diff.
(95% CI)
30-day
Composite
ischaemia
7.3
7.7
0.48
(-0.60, 1.55)
7.8
0.55
(-0.53, 1.63)
Death
1.3
1.5
0.17
(-0.31, 0.66)
1.6
0.26
(-0.23, 0.75)
MI
4.9
5.0
0.04
(-0.84, 0.93)
5.4
0.45
(-0.46, 1.35)
Unplanned
revasc.
2.3
2.7
0.39
(-0.24, 1.03)
2.4
0.10
(-0.51, 0.72)
1-year
Composite
ischaemia
15.3
15.9
0.65
(-0.83, 2.13)
16.0
0.71
(-0.77, 2.19)
Death
3.9
3.8
0.04
(-0.83, 0.74)
3.7
-0.18
(-0.96, 0.60)
MI
6.8
7.0
0.19
(-0.84, 1.23)
7.6
0.83
(-0.22, 1.89)
Unplanned
revasc.
8.1
8.8
0.78
(-0.36, 1.92)
8.4
0.37
(-0.75, 1.50)
14
Table 6. ACUITY trial; 30-day and 1-year risk differences for the composite ischaemic
endpoint and its components for patients that received aspirin and clopidogrel as
per protocol*
Patients receiving aspirin & clopidogrel as per protocol*
Arm A
UFH/enox
+GP IIb/IIIa
inhibitor
(N=2,842)
%
Arm B
bival +GP
IIb/IIIa
inhibitor
(N=2,924)
%
B – A
Risk diff.
(95% CI)
Arm C
bival
alone
(N=2,911)
%
C – A
Risk diff.
(95% CI)
30-day
Composite
ischaemia
7.4
7.4
0.03
(-1.32, 1.38)
7.0
-0.35
(-1.68, 0.99)
Death
1.4
1.4
-0.00
(-0.60, 0.60)
1.2
-0.14
(-0.72, 0.45)
MI
4.8
4.9
0.04
(-1.07, 1.14)
4.7
-0.08
(-1.18, 1.02)
Unplanned
revasc.
2.6
2.8
0.23
(-0.61, 1.08)
2.2
-0.41
(-1.20, 0.39)
1-year
Composite
ischaemia
16.1
16.8
0.68
(-1.24, 2.59)
15.8
-0.35
(-2.24, 1.54)
Death
3.7
3.9
0.20
(-0.78, 1.19)
3.3
-0.36
(-1.31, 0.59)
MI
6.7
7.3
0.60
(-0.71, 1.91)
6.8
0.19
(-1.11, 1.48)
Unplanned
revasc.
9.4
10.0
0.59
(-0.94, 2.12)
8.9
-0.53
(-2.02, 0.96)
*clopidogrel pre-angiography or pre-PCI
The incidence of both ACUITY-scale and TIMI-scale bleeding events up to day 30 for the intent-to-
treat population is presented in Table 8. The incidence of both ACUITY-scale and TIMI-scale
bleeding events to day 30 for the per protocol population are presented in Table 9. The advantage of
bivalirudin over UFH/enoxaparin plus GP IIb/IIIa inhibitor in terms of bleeding events was only
observed in the bivalirudin monotherapy arm.
The
REPLACE-2 Trial
(Patients undergoing PCI)
The 30-day results based on quadruple and triple endpoints from a randomized, double-blind trial of
over 6,000 patients undergoing PCI (REPLACE-2) are shown in Table 7. Bleeding definitions and
outcomes from the REPLACE-2 trial are shown in Table 8.
15
Table 7. REPLACE-2 study results: 30-day endpoints (intent-to-treat and per-protocol
populations
Intent-to-treat
Per-protocol
heparin
heparin
Endpoint
bivalirudin
(N=2,994)
%
+
GP IIb/IIIa
inhibitor
(N=3,008)
%
bivalirudin
(N=2,902)
%
+
GP IIb/IIIa
inhibitor
(N=2,882)
%
Quadruple endpoint
9.2
10.0
9.2
10.0
Triple endpoint*
7.6
7.1
7.8
7.1
Components:
Death
0.2
0.4
0.2
0.4
Myocardial Infarction
7.0
6.2
7.1
6.4
Major bleeding**
(based on non-TIMI
criteria - see section
4.8)
2.4
4.1
2.2
4.0
Urgent
revascularisation
1.2
1.4
1.2
1.3
* excludes major bleeding component. **p
<
0.001
Table 8. Major bleeding rates in clinical trials of bivalirudin 30 day endpoints for intent-to-treat
populations
Bivalirudin (%)
Bival +
GP
IIb/IIIa
inhibitor
(%)
UFH/Enox
1
+ GP IIb/IIIa
inhibitor (%)
REPLACE
-2
ACUITY HORIZONS ACUITY REPLACE
-2
ACUITY HORIZONS
N = 2,994 N = 4,612 N = 1,800 N = 4,604 N = 3,008 N = 4,603 N = 1,802
Protocol
defined
major
bleeding
2.4
3.0
5.1
5.3
4.1
5.7
8.8
TIMI
Major
(non-
CABG)
Bleeding
0.4
0.9
1.8
1.8
0.8
1.9
3.2
1
Enoxaparin was used as comparator in ACUITY only.
16
Table 9. ACUITY trial; bleeding events up to day 30 for the population of patients who received
aspirin and clopidogrel as per protocol*
UFH/enox + GP IIb/IIIa
inhibitor (N= 2,842) %
Bival + GP IIb/IIIa
inhibitor (N=2,924)
%
Bival alone
(N=2,911) %
ACUITY scale major
bleeding
5.9
5.4
3.1
TIMI scale major
bleeding
1.9
1.9
0.8
*clopidogrel pre-angiography or pre-PCI
Bleeding Definitions
REPLACE-2
major bleeding was defined as the occurrence of any of the following: intracranial
haemorrhage, retroperitoneal haemorrhage, blood loss leading to a transfusion of at least two units of
whole blood or packed red blood cells, or bleeding resulting in a haemoglobin drop of more than
3 g/dl, or a fall in haemoglobin greater than 4 g/dl (or 12% of haematocrit) with no bleeding site
identified.
ACUITY major bleeding
was defined as any one of the following: intracranial,
retroperitoneal, intraocular, access site haemorrhage requiring radiological or surgical intervention, ≥5
cm diameter haematoma at puncture site, reduction in haemoglobin concentration of ≥4 g/dl without
an overt source of bleeding, reduction in haemaglobin concentration of ≥3 g/dl with an overt source of
bleeding, re-operation for bleeding, use of any blood product transfusion.
Major bleeding in the
HORIZONS study
was also defined using the ACUITY scale.
TIMI major bleeding
was defined as
intracranial bleeding or a decrease in haemoglobin concentration ≥5 g/dl.
Heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia-thrombosis
syndrome (HIT/HITTS)
Clinical trials in a small number of patients have provided limited information about the use of Angiox
in patients with HIT/HITTS.
5.2 Pharmacokinetic properties
The pharmacokinetic properties of bivalirudin have been evaluated and found to be linear in patients
undergoing Percutaneous Coronary Intervention and in patients with ACS.
Absorption:
The bioavailability of bivalirudin for intravenous use is complete and immediate. The
mean steady-state concentration of bivalirudin following a constant intravenous infusion of
2.5 mg/kg/h is 12.4 µg/ml.
Distribution:
Bivalirudin is rapidly distributed between plasma and extracellular fluid. The steady-state
volume of distribution is 0.1 l/kg. Bivalirudin does not bind to plasma proteins (other than thrombin)
or to red blood cells.
Biotransformation:
As a peptide, bivalirudin is expected to undergo catabolism to its constituent amino
acids, with subsequent recycling of the amino acid in the body pool. Bivalirudin is metabolized by
proteases, including thrombin. The primary metabolite resulting from the cleavage of Arg
3
-Pro
4
bond
of the N-terminal sequence by thrombin is not active because of the loss of affinity to the catalytic
active site of thrombin. About 20% of bivalirudin is excreted unchanged in the urine.
Elimination:
The concentration-time profile following intravenous administration is well described by
a two-compartment model. Elimination follows a first order process with a terminal half-life of 25
±
12 minutes in patients with normal renal function. The corresponding clearance is about 3.4
±
0.5 ml/min/kg.
17
Hepatic Insufficiency:
The pharmacokinetics of bivalirudin have not been studied in patients with
hepatic impairment but are not expected to be altered because bivalirudin is not metabolized by liver
enzymes such as cytochrome P-450 isozymes.
Renal Insufficiency:
The systemic clearance of bivalirudin decreases with glomerular filtration rate
(GFR). The clearance of bivalirudin is similar in patients with normal renal function and those with
mild renal impairment. Clearance is reduced by approximately 20% in patients with moderate or
severe renal impairment, and 80% in dialysis-dependent patients (Table 10).
Table 10. Pharmacokinetic parameters for bivalirudin in patients with normal and impaired
renal function
Renal function (GFR)
Clearance
(ml/min/kg)
Half-life (minutes)
Normal renal function (≥ 90ml/min)
3.4
25
Mild renal impairment (60-89 ml/min)
3.4
22
Moderate renal impairment (30-59 ml/min)
2.7
34
Severe renal impairment (10-29 ml/min)
2.8
57
Dialysis dependent patients (off-dialysis)
1.0
3.5 hours
In patients with renal insufficiency, coagulation parameters such as the ACT should be monitored
during Angiox therapy.
Elderly:
Pharmacokinetics have been evaluated in elderly patients as part of a renal pharmacokinetic
study. Dose adjustments for this age group should be on the basis of renal function, see section 4.2.
Gender:
There are no gender effects in the pharmacokinetics of bivalirudin.
Weight:
Bivalirudin dose is body weight adjusted in mg/kg.
5.3 Pre-clinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety,
pharmacology, repeated dose toxicity, genotoxicity, or toxicity to reproduction.
Toxicity in animals upon repeated or continuous exposure (1 day to 4 weeks at exposure levels of up
to 10
times the clinical steady state plasma concentration) was limited
to exaggerated pharmacological
effects. Comparison of the single and repeated dose studies revealed that toxicity was related primarily
to duration of exposure. All the undesirable effects, primary and secondary, resulting from excessive
physiological stress in response to a non-homeostatic state of coagulation were not seen after short
exposure comparable to that in clinical use, even at much higher doses.
Bivalirudin is intended for short-term administration and therefore no data on the long-term
carcinogenic potential of bivalirudin are available. However, bivalirudin was not mutagenic or
clastogenic in standard assays for such effects.
6.
6.1 List of excipients
Mannitol
Sodium hydroxide solution (for pH adjustment).
18
6.2 Incompatibilities
The following medicinal products should not be administered in the same intravenous line as
bivalirudin since they result in haze formation, micro-particulate formation or gross precipitation;
alteplase, amiodarone HCl, amphotericin B, chlorpromazine HCl, diazepam, prochlorperazine
edisylate, reteplase, streptokinase and vancomycin HCl.
The following six drugs show dose-concentration incompatibilities with bivalirudin. Table 11
summarises compatible and incompatible concentrations of these compounds. The medicinal products
incompatible with bivalirudin at higher concentrations are: dobutamine hydrochloride, famotidine,
haloperidol lactate, labetalol hydrochloride, lorazepam and promethazine HCl.
Table 11. Drugs with dose concentration incompatibilities to bivalirudin.
Drugs with dose concentration
incompatibilities
Compatible concentrations
Incompatible concentrations
Dobutamine HCl
4 mg/ml
12.5 mg/ml
Famotidine
2 mg/ml
10 mg/ml
Haloperidol lactate
0.2 mg/ml
5 mg/ml
Labetalol HCl
2 mg/ml
5 mg/ml
Lorazepam
0.5 mg/ml
2 mg/ml
Promethazine HCl
2 mg/ml
25 mg/ml
6.3 Shelf life
4 years
Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at
2-8
o
C.
Diluted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 25
o
C.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 24 hours at 2–8
o
C unless reconstitution/dilution has taken place in
controlled and validated aseptic conditions.
6.4 Special precautions for storage
Lyophilised powder: Do not store above 25
°
C.
Reconstituted solution: Store in a refrigerator (2–8
o
C). Do not freeze.
Diluted solution: Do not store above 25
°
C. Do not freeze.
6.5 Nature and contents of container
Angiox is supplied as a lyophilised powder in 10 ml single use glass vials (Type 1) closed with a butyl
rubber stopper and sealed with a crimped aluminum seal.
Angiox is available in packs of 2 and 10 vials.
Not all pack sizes may be marketed.
19
6.6 Special precautions for disposal and other handling
Instructions for preparation
Aseptic procedures should be used for the preparation and administration of Angiox.
Add 5 ml sterile water for injections to one vial of Angiox and swirl gently until completely dissolved
and the solution is clear.
Withdraw 5 ml from the vial, and further dilute in a total volume of 50 ml of glucose solution for
injection 5%, or sodium chloride 9 mg/ml (0.9%) solution for injection to give a final bivalirudin
concentration of 5 mg/ml.
The reconstituted/diluted solution should be inspected visually for particulate matter and
discolouration. Solutions containing particulate matter should not be used.
The reconstituted/diluted solution will be a clear to slightly opalescent, colourless to slightly yellow
solution.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
The Medicines Company UK Ltd
115L Milton Park
Abingdon
Oxfordshire
OX14 4SA
UNITED KINGDOM
8.
EU/1/04/289/001-002
9.
20.09.2004/20.09.2009
Detailed information on this product is available on the web site of the European Medicines Agency
(EMEA) http://www.emea.europa.eu
20
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
21
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Hälsa Pharma GmbH, Immermannstraße 9, 33619 Bielefeld, GERMANY
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 8 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by the
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 EMEA.
22
ANNEX III
LABELLING AND PACKAGE LEAFLET
23
A. LABELLING
24
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (pack of 2 vials).
1.
Angiox 250 mg powder for concentrate for solution for injection or infusion
bivalirudin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 vial contains 250 mg bivalirudin.
After reconstitution 1 ml contains 50 mg bivalirudin.
After dilution 1ml contains 5 mg bivalirudin.
3.
LIST OF EXCIPIENTS
Mannitol, sodium hydroxide 2%.
4.
Powder for concentrate for solution for injection or infusion
2 vials
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use
Intravenous use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
25
9.
SPECIAL STORAGE CONDITIONS
Lyophilised powder: Do not store above 25
°
C.
Reconstituted solution: Store in a refrigerator (2 – 8
o
C). Do not freeze.
Diluted solution: Do not store above 25
°
C. Do not freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused solution should be discarded.
The Medicines Company UK Ltd
115L Milton Park
Abingdon
Oxfordshire
OX14 4SA
UNITED KINGDOM
EU/1/04/289/002
13. BATCH NUMBER
Lot {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
26
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (pack of 10 vials).
1.
Angiox 250 mg powder for concentrate for solution for injection or infusion
bivalirudin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 vial contains 250 mg bivalirudin.
After reconstitution 1 ml contains 50 mg bivalirudin.
After dilution 1ml contains 5 mg bivalirudin.
3.
LIST OF EXCIPIENTS
Mannitol, sodium hydroxide 2%
4.
Powder for concentrate for solution for injection or infusion
10 vials
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
27
9.
SPECIAL STORAGE CONDITIONS
Lyophilised powder: Do not store above 25
°
C.
Reconstituted solution: Store in a refrigerator (2 – 8
o
C). Do not freeze.
Diluted solution: Do not store above 25
°
C. Do not freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused solution should be discarded.
The Medicines Company UK Ltd
115L Milton Park
Abingdon
Oxfordshire
OX14 4SA
UNITED KINGDOM
EU/1/04/289/001
13. BATCH NUMBER
Lot {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
28
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
Angiox 250 mg powder for concentrate for solution for injection or infusion
bivalirudin
Intravenous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
250 mg
6.
OTHER
29
B. PACKAGE LEAFLET
30
PACKAGE LEAFLET: INFORMATION FOR THE USER
Angiox 250 mg powder for concentrate for solution for injection and infusion
bivalirudin
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet:
1.
What Angiox is and what it is used for
2.
Before you are given Angiox
3.
How Angiox is used
4.
Possible side effects
5.
How to store Angiox
6.
Further information
1. WHAT ANGIOX IS AND WHAT IT IS USED FOR
Angiox
contains a substance called bivalirudin which
is an antithrombotic medicine. Antithrombotics
are medicines which prevent the formation of blood clots (thrombosis).
Angiox
is used to treat patients
:
•
with chest pain due to heart disease (acute coronary syndromes - ACS)
•
who are having surgery to treat blockages in their blood vessels (angioplasty and/or
percutaneous coronary intervention - PCI).
2.
BEFORE YOU ARE GIVEN ANGIOX
Do not use Angiox
-
if you are allergic (hypersensitive) to bivalirudin or any of the other ingredients of Angiox (See
section 6 for a list of these) or hirudins.
-
if you have, or have recently had, any bleeding from your stomach, intestines, bladder or other
organs, for example, if you have noticed abnormal blood in your stools or urine (except from
menstrual bleeding).
-
if you have, or have had, difficulty with your blood clotting (a low platelet count).
-
if you have severe high blood pressure.
-
if you have an infection of the heart tissue.
-
if you have severe kidney problems or if you need kidney dialysis.
Check with the doctor if you are unsure.
Take special care with Angiox
•
if bleeding occurs (if this happens, treatment with Angiox will be stopped). Throughout your
treatment, the doctor will check you for any signs of bleeding.
31
-
If you have further questions, ask your doctor.
•
if you have been treated before with medicines similar to Angiox (e.g. lepirudin).
•
before the start of the injection or infusion, the doctor will tell you about the signs of allergic
reaction. Such a reaction is rare (affects 1 to 10 users in 10,000).
•
if you are having radiation treatment in the vessels that supply blood to the heart (treatment
called beta or gamma brachytherapy).
•
if you are a child (less than 18 years of age), as this medicine is not appropriate for you.
Taking other medicines
Please tell your doctor
•
if you are taking, or have recently taken, any other medicines, including medicines obtained
without a prescription.
•
If you are taking blood thinners (anticoagulants e.g. warfarin) or medicines to prevent blood
clots (antithrombotics).
Because these medicines may increase the risk of side effects such as bleeding when given at the same
time as Angiox.
Pregnancy and breast-feeding
You
must
tell the doctor if
:
•
you are pregnant or think you may be pregnant
•
you are planning to become pregnant
•
you are breast-feeding.
Angiox should not be used during pregnancy, unless clearly necessary. Your doctor will decide
whether or not this treatment is appropriate for you.
If you are breast-feeding, the doctor will decide whether Angiox should be used.
Driving and using machines
No studies of the effects on the ability to drive and use machines have been performed, but the effects
of this medicine are known to be short-term. Angiox is only given when a patient is in hospital. It is,
therefore, unlikely to affect your ability to drive or to use machines.
3.
HOW ANGIOX IS USED
Your treatment with Angiox will be supervised by a doctor. The doctor will decide how much Angiox
you receive, and will prepare the medicine.
Angiox is for injection, followed by infusion (drip), into a vein (never into a muscle). This is
administered and supervised by a doctor experienced in caring for patients with heart disease.
The dose given depends on your weight and on the kind of treatment you are being given.
Dosage
For patients with acute coronary syndromes (ACS)
the recommended
starting dose
is
:
•
0.1 mg/kg
body weight as an injection, followed by an infusion (drip) of
0.25 mg/kg
body
weight per hour.
If,
after this,
you then need percutaneous coronary intervention (PCI) treatment, the dosage will be
increased to:
32
•
0.5 mg/kg
body weight for the injection, followed by an infusion of
1.75 mg/kg
body weight,
per hour.
•
When this treatment is finished, the infusion may go back to
0.25 mg/kg
body weight, per hour.
If you need to have a coronary artery bypass graft operation, treatment with bivalirudin will either be
stopped one hour before the operation or an additional dose of
0.5 mg/kg
body weight will be given
by injection followed by an infusion of
1.75 mg/kg
body weight per hour.
For patients starting with percutaneous coronary intervention (PCI)
the recommended dose is:
•
0.75 mg/kg
body weight as an injection, followed immediately by an infusion of
1.75 mg/kg
body weight, per hour. (The infusion may continue for up to 4 hours).
If you have mild kidney problems, the dose of Angiox may need to be reduced.
The doctor will decide for how long you should be treated.
If you receive more of this medicine than you should
Your doctor will decide how to treat you, including stopping the drug and monitoring for signs of ill
effects.
If you have any further questions on the use of this product, ask your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Angiox can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, which are defined as follows:
very common: affects more than 1 user in 10
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
very rare: affects less than 1 user in 10,000
not known: frequency cannot be estimated from the available data.
If side effects occur, they may need medical attention.
The most common, important side effect of treatment with Angiox, is bleeding which could occur
anywhere in the body. This can become serious, and may,
rarely
, be fatal. Bleeding is more likely to
occur when Angiox is used in combination with other anticoagulant or antithrombotic medicines (see
section 2 ‘Taking other medicines’).
If you get any of the following, potentially serious, side effects:
o
while you are in hospital: tell the doctor or nurse immediately –
o
after you’ve left hospital: go immediately to the Emergency Department of your nearest
hospital -
•
Bleeding –
a
very
common
side effect.
This could result in complications such as anaemia (a
low blood cell count) or haematoma (bruising).
•
Allergic
reactions,
such as hives (nettle rash), itching all over your body, tightness of the chest.
These are
uncommon
reactions that may be serious or even fatal.
•
Thrombosis
(blood clots) a
common
side effect which may result in serious or fatal
complications such as heart attack.
33
•
Bleeding and bruising at the puncture site
(after PCI treatment) which may be painful. These
side effects are
common
.
If you get any of the following, (potentially less serious), side effects:
o
while you are in hospital: tell the doctor or nurse -
o
after you’ve left hospital: go immediately to the Emergency Department of your nearest
hospital -
Uncommon side effects:
-
severe
bruising (which may be due to a reduction in the number of platelets in
your blood. This
may prevent your blood from clotting as well as it should)
-
headache
- changes in blood pressure
- changes in the rate of your heart beat
- nausea (feeling sick) and/or vomiting (being sick)
- back pain
- chest pain
- shortness of breath
- rash
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet,
please tell your doctor.
5.
HOW TO STORE ANGIOX
Keep out of the reach and sight of children.
Angiox is not to be used after the expiry date which is stated on the label and carton after ‘EXP’. The
expiry date refers to the last day of that month.
Lyophilised (freeze-dried) powder: Do not store above 25
°
C.
Reconstituted solution
:
Store in a refrigerator (2–8
o
C). Do not freeze.
Diluted solution: Do not store above 25ºC. Do not freeze.
The solution should be a clear to slightly opalescent, colourless to slightly yellow solution.
The doctor will check the solution and will discard it, if it contains particles or is discoloured.
6.
FURTHER INFORMATION
What Angiox contains
-
The active substance is bivalirudin.
-
Each vial contains 250 mg bivalirudin.
-
After reconstitution 1ml contains 50 mg bivalirudin.
-
After dilution 1ml contains 5 mg bivalirudin.
The other ingredients are mannitol and sodium hydroxide (for pH adjustment)
What Angiox looks like and contents of the pack
Angiox
is a white to off-white powder in a glass vial.
Angiox is available in cartons containing 2 and 10 vials.
Not all pack sizes may be marketed.
34
Marketing Authorisation Holder
The Medicines Company UK Limited
115L Milton Park
Abingdon
Oxfordshire
OX14 4SA
UNITED KINGDOM
Manufacturer
Hälsa Pharma GmbH
Immermannstraße 9
33619 Bielefeld
GERMANY
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
The Medicines Company UK Ltd
Tél/Tel : + 800 843 633 26
ou/oder +41 61 564 1320
Email/E-Mail : Qchs.mi@quintiles.com
Luxembourg/Luxemburg
The Medicines Company UK Ltd
Tél/Tel : + 800 843 633 26
ou/oder +41 61 564 1320
Email/E-Mail : Qchs.mi@quintiles.com
България
The Medicines Company UK Ltd
Teл.: + 800 843 633 26
или +41 61 564 1320
e-mail: Qchs.mi@quintiles.com
Magyarország
The Medicines Company UK Ltd
Tel. : + 800 843 633 26
vagy +41 61 564 1320
E-mail : Qchs.mi@quintiles.com
Česká republika
The Medicines Company UK Ltd
Tel.: + 800 843 633 26
nebo +41 61 564 1320
E-mail: Qchs.mi@quintiles.com
Malta
The Medicines Company UK Ltd
Tel : + 800 843 633 26
jew +41 61 564 1320
Email : Qchs.mi@quintiles.com
Danmark
The Medicines Company UK Ltd
Tlf.nr.: + 800 843 633 26
eller +41 61 564 1320
E-mail : Qchs.mi@quintiles.com
Nederland
The Medicines Company UK Ltd
Tel : + 800 843 633 26
of +41 61 564 1320
Email : Qchs.mi@quintiles.com
Deutschland
The Medicines Company UK Ltd
Tel : + 800 843 633 26
oder +41 61 564 1320
E-Mail : Qchs.mi@quintiles.com
Norge
The Medicines Company UK Ltd
Tlf.: + 800 843 633 26
eller +41 61 564 1320
E-post: Qchs.mi@quintiles.com
Eesti
The Medicines Company UK Ltd
Tel. : + 800 843 633 26
või +41 61 564 1320
E-mail: Qchs.mi@quintiles.com
Österreich
The Medicines Company UK Ltd
Tel : + 800 843 633 26
oder +41 61 564 1320
E-Mail : Qchs.mi@quintiles.com
35
Ελλάδα
Ferrer-Galenica A.E.
Τηλ: +30 210 5281700
Polska
The Medicines Company UK Ltd
Tel.: + 800 843 633 26
lub +41 61 564 1320
Τηλ: +30 210 5281700
E-mail: Qchs.mi@quintiles.com
España
Ferrer Farma, S.A.
Tel.: +34 93 600 37 00
Portugal
Ferrer Azevedos, S.A.
Tel.: +351 21 47 25 900
France
The Medicines Company France SAS
Tél : + 800 843 633 26
ou + 33 1 47 55 30 70
Email : Qchs.mi@quintiles.com
România
The Medicines Company UK Ltd
Tel: + 800 843 633 26
sau +41 61 564 1320
E-mail : Qchs.mi@quintiles.com
Ireland
The Medicines Company UK Ltd
Tel : + 800 843 633 26
or +41 61 564 1320
Email : Qchs.mi@quintiles.com
Slovenija
The Medicines Company UK Ltd
Tel : + 800 843 633 26
ali +41 61 564 1320
E-pošta: Qchs.mi@quintiles.com
Ísland
The Medicines Company UK Ltd
Sími : + 800 843 633 26
eða +41 61 564 1320
Netfang : Qchs.mi@quintiles.com
Slovenská republika
The Medicines Company UK Ltd
Tel : + 800 843 633 26
alebo +41 61 564 1320
Email : Qchs.mi@quintiles.com
Italia
The Medicines Company UK Ltd
Tel: + 800 843 633 26
o +41 61 564 1320
Email: Qchs.mi@quintiles.com
Suomi/Finland
The Medicines Company UK Ltd
Puh./tel. + 800 8436 3326
tai +41 61 564 1320
S-posti: Qchs.mi@quintiles.com
Κύπρος
The Medicines Company UK Ltd
Τηλ: + 800 843 633 26
or +41 61 564 1320
Email : Qchs.mi@quintiles.com
Sverige
The Medicines Company UK Ltd
Tfn : + 800 843 633 26
eller +41 61 564 1320
E-post : Qchs.mi@quintiles.com
Latvija
The Medicines Company UK Ltd
Tālr. + 800 843 633 26
vai +41 61 564 1320
E-pasts: Qchs.mi@quintiles.com
United Kingdom
The Medicines Company UK Ltd
Tel : + 800 843 633 26
or +41 61 564 1320
Email : Qchs.mi@quintiles.com
Lietuva
The Medicines Company UK Ltd
Tel. Nr.: + 800 843 633 26
arba +41 61 564 1320
El. paštas: Qchs.mi@quintiles.com
This leaflet was last approved in:
36
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.emea.europa.eu
37
Source: European Medicines Agency
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