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AGGRASTAT 250 MCG/ML CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance(s): TIROFIBAN HYDROCHLORIDE MONOHYDRATE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
AGGRASTAT® (250 micrograms/ml) concentrate for solution for infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of concentrate for solution for infusion contains 281 micrograms of tirofiban
hydrochloride monohydrate which is equivalent to 250 micrograms tirofiban.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Concentrate for solution for infusion (50 ml vial).
A clear, colourless concentrated solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Aggrastat is indicated for the prevention of early myocardial infarction in adult
patients presenting with acute coronary syndromes without ST elevation
(NSTE-ACS) with the last episode of chest pain occurring within 12 hours and
with ECG changes and/or elevated cardiac enzymes.
Patients most likely to benefit from Aggrastat treatment are those at high risk
of developing myocardial infarction within the first 3-4 days after onset of
acute angina symptoms including for instance those that are likely to undergo
an early percutaneous coronary intervention (PCI). Aggrastat is also indicated
for the reduction of major cardiovascular events in patients with acute
myocardial infarction (STEMI) intended for primary PCI (see sections 4.2 and
5.1)
Aggrastat is intended for use with acetylsalicylic acid (ASA) and
unfractionated heparin.

4.2

Posology and method of administration
This product is for hospital use only, by specialist physicians experienced in
the management of acute coronary syndromes.
Aggrastat Concentrate must be diluted before use.
Aggrastat should be administered with unfractionated heparin and oral
antiplatelet therapy, including ASA.

Posology
In patients who are managed with an early invasive strategy for NSTE-ACS
but not planned to undergo angiography for at least 4 hours and up to 48 hours
after diagnosis, Aggrastat is given intravenously at an initial infusion rate of
0.4 microgram/kg/min for 30 minutes. At the end of the initial infusion,
Aggrastat should be continued at a maintenance infusion rate of
0.1 microgram/kg/min. Aggrastat should be given with unfractionated heparin
(usually an intravenous bolus of 50-60 units [U]/kg simultaneously with the
start of Aggrastat therapy, then approximately 1,000 U per hour, titrated on the
basis of the activated thromboplastin time [APTT], which should be about
twice the normal value) and oral antiplatelet therapy, including but not limited
to ASA (see section 5.1), unless contra-indicated.
In NSTE-ACS patients planned to undergo PCI within the first 4 hours of
diagnosis or in patients with acute myocardial infarction intended for primary
PCI, Aggrastat should be administered utilizing an initial bolus of 25
microgram/kg given over a 3 minute period, followed by a continuous infusion
at a rate of 0.15 microgram/kg/min for 12-24, and up to 48 hours. Aggrastat
should be administered with unfractionated heparin (dosage as above) and oral
antiplatelet therapy, including but not limited to ASA (see section 5.1), unless
contra-indicated.
Elderly
No dosage adjustment is necessary for the elderly (see section 4.4).
Patients with severe kidney failure
In severe kidney failure (creatinine clearance <30ml/min) the dosage of
Aggrastat should be reduced by 50% (see sections 4.4 and 5.2).
Paediatric population
The safety and efficacy of Aggrastat in children aged <18 years have not been
established.
No data are available.
Table 1 is provided as a guide to dosage adjustment by weight.
Aggrastat Concentrate must be diluted to the same strength as Aggrastat
Solution, as noted under Instructions for Use.
Table 1: Dosing Table

Patient
Weight
(kg)

0.4 microgram/kg/min
Loading Dose Regimen
Most Patients
30 min
Maintenance
Loading
Infusion
Rate
Infusion
(ml/hr)
Rate
(ml/hr)

0.4 microgram/kg/min
Loading Dose Regimen
Severe Kidney Failure
Maintenance
30 min
Infusion
Loading
Rate
Infusion
(ml/hr)
Rate
(ml/hr)

25 microgram/kg
Dose Bolus Regimen
Most Patients
Bolus
Maintenance
Infusion
(ml)
Rate

25 microgram/kg
Dose Bolus Regimen
Severe Kidney Failure
Bolus
Maintenance
Infusion
(ml)
Rate
(ml/hr)

(ml/hr)

30-37

16

4

8

2

17

6

8

3

38-45

20

5

10

3

21

7

10

4

46-54

24

6

12

3

25

9

13

5

55-62

28

7

14

4

29

11

15

5

Patient
Weight
(kg)

0.4 microgram/kg/min
Loading Dose Regimen
Most Patients
Maintenance
30 min
Infusion
Loading
Rate
Infusion
(ml/hr)
Rate
(ml/hr)

0.4 microgram/kg/min
Loading Dose Regimen
Severe Kidney Failure
Maintenance
30 min
Infusion
Loading
Rate
Infusion
(ml/hr)
Rate
(ml/hr)

25 microgram/kg
Dose Bolus Regimen
Most Patients
Bolus
Maintenance
Infusion
(ml)
Rate

25 microgram/kg
Dose Bolus Regimen
Severe Kidney Failure
Bolus
Maintenance
Infusion
(ml)
Rate

(ml/hr)

(ml/hr)

63-70

32

8

16

4

33

12

17

6

71-79

36

9

18

5

38

14

19

7

80-87

40

10

20

5

42

15

21

8

88-95

44

11

22

6

46

16

23

8

96-104

48

12

24

6

50

18

25

9

105-112

52

13

26

7

54

20

27

10

113-120

56

14

28

7

58

21

29

10

121-128

60

15

30

8

62

22

31

11

129-137

64

16

32

8

67

24

33

12

138-145

68

17

34

9

71

25

35

13

146-153

72

18

36

9

75

27

37

13

Start and duration of therapy with Aggrastat
In patients who are managed with an early invasive strategy for NSTE-ACS
but not planned to undergo angiography for at least 4 hours and up to 48 hours
after diagnosis, Aggrastat 0.4 microgram/kg/min loading dose regimen should
be initiated upon diagnosis. The recommended duration of the maintenance
infusion should be at least 48 hours. Infusion of Aggrastat and unfractionated
heparin may be continued during coronary angiography and should be
maintained for at least 12 hours and not more than 24 hours after
angioplasty/atherectomy. Once a patient is clinically stable and no coronary
intervention procedure is planned by the treating physician, the infusion
should be discontinued. The entire duration of treatment should not exceed
108 hours.
If the patient diagnosed with NSTE-ACS and managed with an invasive
strategy undergoes angiography within 4 hours after the diagnosis, the
Aggrastat 25 microgram/kg dose bolus regimen should be initiated at the start
of PCI with the infusion continued for 12-24 hours and up to 48 hours.
In patients with acute myocardial infarction intended for primary PCI, the 25
microgram/kg dose bolus regimen should be initiated as soon as possible after
diagnosis.
Concurrent therapy (unfractionated heparin, oral antiplatelet therapy,
including ASA)
Treatment with unfractionated heparin is initiated with an i.v. bolus of 50-60
U/kg and then continued with a maintenance infusion of 1,000 U per hour. The
heparin dosage is titrated to maintain an APTT of approximately twice the
normal value.

Unless contra-indicated, all patients should receive oral antiplatelet agents,
including but not limited to ASA, before the start of Aggrastat (see section
5.1). This medication should be continued at least for the duration of the
infusion of Aggrastat.
Most studies investigating the administration of Aggrastat as an adjunct to PCI
have used ASA in combination with clopidogrel as oral antiplatelet therapy.
The efficacy of the combination of Aggrastat with either prasugrel or
ticagrelor has not been established in randomised controlled trials.
If angioplasty (PCI) is required, heparin should be stopped after PCI, and the
sheaths should be withdrawn once coagulation has returned to normal, e.g.
when the activated clotting time (ACT) is less than 180 seconds (usually 2-6
hours after discontinuation of heparin).
Method of administration
Instructions for use
Aggrastat Concentrate must be diluted before use:
1. Draw 50ml from a 250ml container of sterile 0.9% saline or 5% glucose in
water and replace with 50ml Aggrastat (from one 50ml puncture vial) to
make up a concentration of 50 microgram/ml. Mix well before use.
2. Use according to the dosage table above.
FOR BOTH FORMULATIONS
Where the solution and container permit, parenteral drugs should be inspected
for visible particles or discoloration before use.
Aggrastat should only be given intravenously and may be administered with
unfractionated heparin through the same infusion tube.
It is recommended that Aggrastat be administered with a calibrated infusion
set using sterile equipment.
Care should be taken to ensure that no prolongation of the infusion of the
initial dose occurs and that miscalculation of the infusion rates for the
maintenance dose on the basis of the patient’s weight is avoided.

4.3

Contraindications
Aggrastat is contra-indicated in patients who are hypersensitive to the active
substance or to any of the excipients of the preparation listed in section 6.1 or who
developed thrombocytopenia during earlier use of a GP IIb/IIIa receptor antagonist.
Since inhibition of platelet aggregation increases the bleeding risk, Aggrastat is
contra-indicated in patients with:







History of stroke within 30 days or any history of haemorrhagic stroke.
Known history of intracranial disease (e.g. neoplasm, arteriovenous malformation,
aneurysm).
Active or recent (within the previous 30 days of treatment) clinically relevant
bleeding (e.g. gastro-intestinal bleeding).
Malignant hypertension.
Relevant trauma or major surgical intervention within the past six weeks.
Thrombocytopenia (platelet count <100,000/mm3), disorders of platelet function.




4.4

Clotting disturbances (e.g. prothrombin time >1.3 times normal or INR
[International Normalised Ratio] >1.5).
Severe liver failure.

Special warnings and precautions for use
The administration of Aggrastat alone without unfractionated heparin is not
recommended.
There is limited experience with concomitant administration of Aggrastat with
enoxaparin (see sections 5.1 and 5.2). The concomitant administration of Aggrastat
with enoxaparin is associated with a higher frequency of cutaneous and oral bleeding
events, but not in TIMI bleeds**, when compared with the concomitant administration
of Aggrastat and unfractionated heparin. An increased risk of serious bleeding events
associated with the concomitant administration of Aggrastat and enoxaparin cannot be
excluded, particularly in patients given additional unfractionated heparin in
conjunction with angiography and/or PCI. The efficacy of Aggrastat in combination
with enoxaparin has not been established. The safety and efficacy of Aggrastat with
other low molecular weight heparins has not been investigated.
There is insufficient experience with the use of tirofiban hydrochloride in the
following diseases and conditions, however, an increased risk of bleeding is
suspected. Therefore, tirofiban hydrochloride is not recommended in:
• Traumatic or protracted cardiopulmonary resuscitation, organ biopsy or
lithotripsy within the past two weeks
• Severe trauma or major surgery >6 weeks but <3 months previously
• Active peptic ulcer within the past three months
• Uncontrolled hypertension (>180/110mmHg)
• Acute pericarditis
• Active or a known history of vasculitis
• Suspected aortic dissection
• Haemorrhagic retinopathy
• Occult blood in the stool or haematuria
• Thrombolytic therapy (see section 4.5).
• Concurrent use of drugs that increase the risk of bleeding to a relevant degree (see
section 4.5).

There is no therapeutic experience with tirofiban hydrochloride in patients for
whom thrombolytic therapy is indicated. Consequently, the use of tirofiban
hydrochloride is not recommended in combination with thrombolytic therapy.
Aggrastat infusion should be stopped immediately if circumstances arise that
necessitate thrombolytic therapy (including acute occlusion during PCI) or if
the patient must undergo an emergency coronary artery bypass graft (CABG)
operation or requires an intra-aortic balloon pump.
Paediatric population
**

TIMI major bleeds are defined as a haemoglobin drop of >50g/l with or without an
identified site, intracranial haemorrhage, or cardiac tamponade. TIMI minor bleeds are
defined as a haemoglobin drop of >30g/l but ≤50g/l with bleeding from a known site or
spontaneous gross haematuria, haematemesis, or haemoptysis. TIMI “loss no site” is defined
as a haemoglobin drop >40g/l but <50g/l without an identified bleeding site.

There is no therapeutic experience with Aggrastat in children, thus, the use of
Aggrastat is not recommended in these patients.
Other precautionary notes and measures
There are insufficient data regarding the re-administration of Aggrastat.
Patients should be carefully monitored for bleeding during treatment with
Aggrastat. If treatment of haemorrhage is necessary, discontinuation of
Aggrastat should be considered (see section 4.9). In cases of major or
uncontrollable bleeding, tirofiban hydrochloride should be discontinued
immediately.
Aggrastat should be used with special caution in the following conditions and
patient groups:









Recent clinically relevant bleeding (less than one year)
Puncture of a non-compressible vessel within 24 hours before administration of
Aggrastat
Recent epidural procedure (including lumbar puncture and spinal anaesthesia)
Severe acute or chronic heart failure
Cardiogenic shock
Mild to moderate liver insufficiency
Platelet count <150,000/mm3, known history of coagulopathy or platelet function
disturbance or thrombocytopenia
Haemoglobin concentration less than 11 g/dl or haematocrit <34%.

Special caution should be used during concurrent administration of ticlopidine,
clopidogrel, adenosine, dipyridamole, sulfinpyrazone, and prostacyclin.
Efficacy with regard to dose
The administration of a 10 microgram/kg bolus regimen of tirofiban failed to
show noninferiority in clinically relevant endpoints at 30 days compared to
abciximab (see section 5.1).
Elderly patients, female patients, and patients with low body weight
Elderly and/or female patients had a higher incidence of bleeding
complications than younger or male patients, respectively. Patients with a low
body weight had a higher incidence of bleeding than patients with a higher
body weight. For these reasons Aggrastat should be used with caution in these
patients and the heparin effect should be carefully monitored.
Impaired renal function
There is evidence from clinical studies that the risk of bleeding increases with
decreasing creatinine clearance and hence also reduced plasma clearance of
tirofiban. Patients with decreased renal function (creatinine clearance
<60ml/min) should therefore be carefully monitored for bleeding during
treatment with Aggrastat and the heparin effect should be carefully monitored.
In severe kidney failure the Aggrastat dosage should be reduced (see section
4.2).
Femoral artery line
During treatment with Aggrastat there is a significant increase in bleeding
rates, especially in the femoral artery area, where the catheter sheath is
introduced. Care should be taken to ensure that only the anterior wall of the
femoral artery is punctured. Arterial sheaths may be removed when

coagulation has returned to normal, e.g. when activated clotting time (ACT) is
less than 180 seconds, (usually 2–6 hours after discontinuation of heparin).
After removal of the introducer sheath, careful haemostasis should be ensured
under close observation.
General nursing care
The number of vascular punctures, and intramuscular injections should be
minimised during the treatment with Aggrastat. I.V. access should only be
obtained at compressible sites of the body. All vascular puncture sites should
be documented and closely monitored. The use of urinary catheters,
nasotracheal intubation and nasogastric tubes should be critically considered.
Monitoring of laboratory values
Platelet count, haemoglobin and haematocrit levels should be determined
before treatment with Aggrastat as well as within 2-6 hours after start of
therapy with Aggrastat and at least once daily thereafter while on therapy (or
more often if there is evidence of a marked decrease). In patients who have
previously received GPIIb/IIIa receptor antagonists (cross reactivity can
occur), the platelet count should be monitored immediately e.g. within the first
hour of administration after re-exposure (see section 4.8). If the platelet count
falls below 90,000/mm3, further platelet counts should be carried out in order
to rule out pseudothrombocytopenia. If thrombocytopenia is confirmed,
Aggrastat and heparin should be discontinued. Patients should be monitored
for bleeding and treated if necessary (see section 4.9).
In addition, activated thromboplastin time (APTT) should be determined
before treatment and the anticoagulant effects of heparin should be carefully
monitored by repeated determinations of APTT and the dose should be
adjusted accordingly (see section 4.2). Potentially life-threatening bleeding
may occur especially when heparin is administered with other products
affecting haemostasis, such as GPIIb/IIIa receptor antagonists.
Sodium content
Aggrastat Concentrate
Aggrastat concentrate for solution for infusion contains approximately 189mg
of sodium per 50ml vial which should be taken into consideration by patients
on a controlled sodium diet.

4.5

Interaction with other medicinal products and other forms of interaction
The use of several platelet aggregation inhibitors increases the risk of bleeding,
likewise their combination with heparin, warfarin and thrombolytics. Clinical and
biological parameters of haemostasis should be regularly monitored.
The concomitant administration of Aggrastat and ASA increases the inhibition of
platelet aggregation to a greater extent than ASA alone, as measured by ex vivo APDinduced platelet aggregation test. The concomitant administration of Aggrastat and
unfractionated heparin increases the prolongation of the bleeding time to a greater
extent as compared to unfractionated heparin alone.
With the concurrent use of Aggrastat, unfractionated heparin, ASA, and clopidogrel
there was a comparable incidence of bleeding than when only unfractionated heparin,
ASA, and clopidogrel were used together (see sections 4.4 and 4.8).

Aggrastat prolonged bleeding time; however, the combined administration of
Aggrastat and ticlopidine did not additionally affect bleeding time.
Concomitant use of warfarin with Aggrastat plus heparin was associated with an
increased risk of bleeding.
Aggrastat is not recommended in thrombolytic therapy - concurrent or less than 48
hours before administration of tirofiban hydrochloride or concurrent use of drugs that
increase the risk of bleeding to a relevant degree (e.g. oral anticoagulants, other
parenteral GP IIb/IIIa inhibitors, dextran solutions). There is insufficient experience
with the use of tirofiban hydrochloride in these conditions; however, an increased risk
of bleeding is suspected.

4.6

Fertility, pregnancy and lactation
Pregnancy
There are no or limited amount of data from the use of tirofiban hydrochloride in
pregnant women. Animal studies are insufficient with respect to reproductive toxicity
(see section 5.3). Aggrastat is not recommended during pregnancy unless clearly
necessary.
Breastfeeding

It is unknown whether tirofiban hydrochloride is excreted in human milk.
Available pharmacodynamic/toxicological data in animals have shown
excretion of tirofiban hydrochloride in milk (for details see section 5.3). A risk
to the newborn cannot be excluded. A decision must be made whether to
discontinue breastfeeding or to discontinue Aggrastat therapy, taking into
account the benefit of breastfeeding for the child and the benefit of therapy for
the woman.
Fertility
Fertility and reproductive performance were not affected in studies with male and
female rats treated with different doses of tirofiban hydrochloride (see section 5.3).
However, animal studies are insufficient to draw conclusions with respect to
reproductive toxicity in humans.

4.7

Effects on ability to drive and use machines
Not relevant.

4.8

Undesirable effects
a. Summary of safety profile
The most common adverse reaction reported during therapy with Aggrastat,
when used concomitantly with heparin, aspirin and other oral anti-platelet
agents, was bleeding, which usually involved mild mucocutaneous bleeding or
mild catheterization-site bleeding.
Gastro-intestinal, retro-peritoneal, intracranial, haemorrhoidal and postoperative bleeding, epidural haematoma in the spinal region,
haemopericardium and pulmonary (alveolar) haemorrhage have also been
reported. Rates of TIMI major and intracranial bleeding in the pivotal

Aggrastat studies were <2.2% and <0.1%, respectively. The most serious
adverse reaction was fatal bleeding.
In the pivotal studies, administration of Aggrastat was associated with
thrombocytopenia (platelet count <90,000/mm3), occurring in 1.5% of patients
treated with Aggrastat and heparin. The incidence of severe thrombocytopenia
(platelet count <50,000/mm3) was 0.3%. The most common non-bleeding
adverse drug reactions associated with Aggrastat given concurrently with
heparin were nausea (1.7%), fever (1.5%) and headache (1.1%).
b. Tabulated summary of adverse reactions
Table 2 lists the adverse reactions based on experience from six double-blind
controlled clinical studies (including 1953 patients receiving Aggrastat plus
heparin) as well as adverse reactions reported from post-marketing experience.
Within the organ system classes, adverse reactions are listed under headings of
frequency using the following categories: 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). Because post-marketing events are derived from spontaneous
reports from a population of uncertain size, it is not possible to determine their
exact incidence. Therefore, the frequency of these adverse reactions is
categorised as not known.
Table 2: Undesirable effects in clinical studies and from post-marketing
experience.
System Organ
Class

Very common

Common

Uncommon

Not known

Blood and
lymphatic system
disorders

Acute and/or severe
(<20,000/mm3)
decreases in platelet
counts

Immune System
Disorders

Severe allergic
reactions including
anaphylactic
reactions.

Nervous system
disorders

Headache

Intracranial bleeding,
spinal epidural
haematoma

Cardiac disorders
Vascular disorders

Hemopericardium
Haematoma

Respiratory,
thoracic and
mediastinal
disorders

Haemoptysis,
epistaxis

Gastrointestinal
disorders

Nausea

Skin and
subcutaneous
tissue disorders

Ecchymosis

Oral haemorrhage
gingival
haemorrhage

Pulmonary (alveolar)
haemorrhage

GI
haemorrhage,
haematemesis

Retroperitoneal
bleeding

System Organ
Class

Very common

Common

Renal and urinary
disorders

Haematuria

General disorders
and administration
site conditions

Fever

Injury, poisoning
and procedural
complications

Post-operative
haemorrhage*

Vessel puncture
site haemorrhage

Investigations

Occult blood
in stool or
urine

Decreases in
haematocrit and
haemoglobin,
platelet counts
<90,000/mm3

Uncommon

Not known

Platelet counts
<50,000/mm3

*Primarily related to catheterization sites.

c. Description of selected adverse reactions
Bleeding
Both, with the Aggrastat 0.4 microgram/kg/min infusion regimen and the 25
microgram/kg dose bolus regimen, rates of major bleeding complications are
low and not significantly increased.
In the PRISM-PLUS study, using the Aggrastat 0.4 microgram/kg/min
infusion regimen, the incidence of TIMI major bleeding was 1.4% for
Aggrastat in combination with heparin and 0.8% for heparin alone. The
incidence of TIMI minor bleeding was 10.5% for Aggrastat in combination
with heparin and 8.0% for heparin alone. The percentage of patients who
received a transfusion was 4.0% for Aggrastat in combination with heparin
and 2.8% for heparin alone.
With the Aggrastat 25 microgram/kg dose bolus regimen, data from the
ADVANCE study suggest that the number of bleeding events is low and does
not seem to be significantly increased compared to placebo. There were no
TIMI major bleedings and no transfusions in either group. TIMI minor
bleeding with the Aggrastat 25 microgram/kg dose bolus regimen was 4% as
compared with 1% in the placebo arm p=0.19).
In the On-TIME 2 study, there were no significant differences in the incidence
of TIMI major bleeding (3.4% vs. 2.9% p =0.58) and TIMI minor bleeding
(5.9% vs. 4.4%; p=0.206) between the Aggrastat 25 microgram/kg dose bolus
regimen and the control arm.
The rates of TIMI major (2.4% vs. 1.6%; p=0.44) or minor bleeding (4.8% vs.
6.2%; p=0.4) were also not significantly different between the Aggrastat 25
microgram/kg dose and the standard dose of abciximab, which were compared
in the MULTISTRATEGY study.
Based upon an assessment of haemorrhagic complications performed in the
context of a meta-analysis (n=4076 ACS patients), the Aggrastat 25
microgram/kg dose bolus regimen does not significantly increase the rates of
major bleeding, or thrombocytopenia, when compared to placebo. When

considering the trials of the Aggrastat 25 microgram/kg bolus regimen
compared with abciximab, individual study results do not demonstrate a
significant difference in major bleeding between the two treatments.
Thrombocytopenia
During Aggrastat therapy, acute decreases in platelet count or
thrombocytopenia occurred more frequently than in the placebo group. These
decreases were reversible upon discontinuation of Aggrastat. Acute and severe
platelet (platelet counts <20,000/mm3) decreases have been observed in
patients with no prior history of thrombocytopenia upon re-administration of
GPIIb/IIIa receptor antagonists and may be associated with chills, low-grade
fever or bleeding complications.
Analysis of the studies comparing the 25 microgram/kg dose bolus regimen
against abciximab yielded a significantly lower rate of thrombocytopenia for
Aggrastat (0.45% vs. 1.7%; OR=0.31; p=0.004).
Allergic reactions
Severe allergic reactions (e.g., bronchospasm, urticaria) including anaphylactic
reactions have occurred during initial treatment (also on the first day) and
during readministration of Aggrastat. Some cases have been associated with
severe thrombocytopenia (platelet counts <10,000/mm3).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard

4.9

Overdose
Inadvertent overdose with tirofiban hydrochloride occurred in the clinical studies, up
to 50 microgram/kg as a three minute bolus or 1.2 microgram/kg/min as an initial
infusion. Overdose with up to 1.47 microgram/kg/min as a maintenance infusion rate
has also occurred.
a) Symptoms of overdose
The symptom of overdose most commonly reported was bleeding, usually
mucosal bleeding and localised bleeding at the arterial puncture site for cardiac
catheterisation but also single cases of intracranial haemorrhages and
retroperitoneal bleedings (see sections 4.4 and 5.1).
b) Measures
Overdose with tirofiban hydrochloride should be treated in accordance with the
patient’s condition and the attending physician’s assessment. If treatment of
haemorrhage is necessary, the Aggrastat infusion should be discontinued.
Transfusions of blood and/or thrombocytes should also be considered. Aggrastat
can be removed by haemodialysis.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Blood and blood forming organs – antithrombotic
agents – antithrombotic agents – Platelet aggregation inhibitors excl. heparin
ATC-Code: B01A C17
Mechanism of action
Tirofiban hydrochloride (tirofiban) is a non-peptidal antagonist of the GP
IIb/IIIa receptor, an important platelet surface receptor involved in platelet
aggregation. Tirofiban prevents fibrinogen from binding to the GP IIb/IIIa
receptor, thus blocking platelet aggregation.
Tirofiban leads to inhibition of platelet function, evidenced by its ability to
inhibit ex vivo ADP-induced platelet aggregation and to prolong bleeding time
(BT). Platelet function returns to baseline within eight hours after
discontinuation.
The extent of this inhibition runs parallel to the tirofiban plasma concentration.
Pharmacodynamic effects
In the 0.4 microgram/kg/min infusion regimen of tirofiban, in the presence of
unfractionated heparin and ASA, tirofiban produced a more than 70% (median
89%) inhibition of ex vivo ADP-induced platelet aggregation in 93% of the
patients, and a prolongation of the bleeding time by a factor of 2.9 during
infusion. Inhibition was achieved rapidly with the 30-minute loading infusion
and was maintained over the duration of the infusion.
The tirofiban 25 microgram/kg dose bolus regimen (followed by 18-24 hour
maintenance infusion of 0.15 microgram/kg/min), in the presence of
unfractionated heparin and oral antiplatelet therapy, produced an average
ADP-induced inhibition of maximal aggregation 15 to 60 minutes after onset
of treatment of 92% to 95% as measured with light transmission aggregometry
(LTA).
Clinical efficacy and safety
PRISM-PLUS study
The double-blind, multicentre, controlled PRISM-PLUS study compared the
efficacy of Aggrastat and unfractionated heparin (n=773) versus
unfractionated heparin (n=797) in patients with unstable angina (UA) or acute
non-Q-wave myocardial infarction (NQWMI) with prolonged repetitive
anginal pain or post-infarction angina, accompanied by new transient or
persistent ST-T wave changes or elevated cardiac enzymes.
Patients were randomised to either Aggrastat (30 minute loading infusion of
0.4 microgram/kg/min followed by a maintenance infusion of 0.10
microgram/kg/min) and heparin (bolus of 5,000 units (U) followed by an
infusion of 1,000 U/hr titrated to maintain an activated partial thromboplastin
time (APTT) of approximately two times control), or heparin alone.
All patients received ASA unless contraindicated. Study drug was initiated
within 12 hours after the last anginal episode. Patients were treated for 48

hours, after which they underwent angiography and possibly
angioplasty/atherectomy, if indicated, while Aggrastat was continued.
Aggrastat was infused for a mean period of 71.3 hours.
The combined primary study end-point was the occurrence of refractory
ischaemia, myocardial infarction or death at seven days after the start of
Aggrastat.
At 7 days, the primary end-point, there was a 32% risk reduction (RR) (12.9%
vs. 17.9%) in the Aggrastat group for the combined end-point (p=0.004): this
represents approximately 50 events avoided for 1,000 patients treated. After
30 days the RR for the composite end-point of death, MI, refractory ischaemic
conditions, or readmissions for UA was 22% (18.5% vs. 22.3%; p=0.029).
After six months the relative risk of composite of death, MI, refractory
ischaemic conditions, or readmissions for UA was reduced by 19% (27.7% vs.
32.1% ; p=0.024).
Regarding the composite of death or MI, at seven days for the Aggrastat group
there was a 43% RR (4.9% vs. 8.3%; p=0.006); at 30 days the RR was 30%
(8.7% vs. 11.9%; p=0.027) and at 6 months the RR was 23% (12.3% vs.
15.3%; p=0.063).
The reduction of MI in patients receiving Aggrastat appeared early during
treatment (within the first 48 hours) and was maintained through 6 months. In
the 30% of patients who underwent angioplasty/atherectomy during initial
hospitalisation, there was a 46% RR (8.8% vs. 15.2%) for the primary
composite endpoint at 30 days as well as a 43% RR (5.9% vs. 10.2%) for
death or MI.
Based on a safety study, the concomitant administration of Aggrastat (30
minute loading dose of [0.4 microgram/kg/min] followed by a maintenance
infusion of 0.1 microgram/kg/min for up to 108 hours) with enoxaparin
(n=315) was compared to the concomitant administration of Aggrastat with
unfractionated heparin (n=210) in patients presenting with UA and NQWMI.
Patients in the enoxaparin group received a 1.0 milligram/kg subcutaneous
injection every 12 hours for a period of at least 24 hours and a maximum
duration of 96 hours. Patients randomised to unfractionated heparin received a
5000-unit intravenous bolus followed by a maintenance infusion of 1000 units
per hour for at least 24 hours and a maximum duration of 108 hours. The total
TIMI bleed rate was 3.5% for the Aggrastat/enoxaparin group and 4.8% for
the Aggrastat/unfractionated heparin group. Although there was a significant
difference in the rates of cutaneous bleeds between the two groups (29.2% in
the enoxaparin converted to unfractionated heparin group and 15.2% in the
unfractionated heparin group), there were no TIMI major bleeds (see section
4.4) in either group. The efficacy of Aggrastat in combination with enoxaparin
has not been established.
PRISM PLUS trial was conducted at a time when the standard of care of
managing acute coronary syndromes was different from that of present times
in terms of oral platelet ADP receptor (P2Y12) antagonists use and the routine
use of intracoronary stents.
ADVANCE study

The ADVANCE study determined the safety and efficacy of the Aggrastat 25
microgram/kg dose bolus regimen as compared with placebo in patients
undergoing elective or urgent PCI who exhibit high-risk characteristics
including the presence of at least one coronary narrowing ≥70% and diabetes,
need for multi-vessel intervention, or NSTE-ACS. All patients received
unfractionated heparin, acetylsalicylic acid (ASA) and a thienopyridine
loading dose followed by maintenance therapy. A total of 202 patients were
randomised to either Aggrastat (25 microgram/kg bolus IV over 3 minutes
followed by a continuous IV infusion of 0.15 microgram/kg/minute for 24-48
hours) or Placebo given immediately before PCI.
The primary endpoint was a composite of death, nonfatal MI, urgent target
vessel revascularization (uTVR), or thrombotic bailout GP IIb/IIIa inhibitor
therapy within a median follow-up of 180 days after the index procedure. The
safety endpoints of major and minor bleeding were defined according to the
TIMI criteria.
In the intent-to-treat population, the cumulative incidence of the primary end
point was 35% and 20% in placebo and Aggrastat groups, respectively (hazard
ratio [HR] 0.51 [95% confidence interval (CI), 0.29 to 0.88]; p=0.01). As
compared with placebo, there was a significant reduction in the composite of
death, MI, or uTVR in the Aggrastat group (31% vs. 20%, HR, 0.57 95% CI,
0.99–0.33]; p=0.048.
EVEREST study
The randomised open-label EVEREST trial compared the upstream 0.4
microgram/kg/min loading dose regimen initiated in the coronary care unit
with the Aggrastat 25 microgram/kg dose bolus regimen or abciximab 0.25
milligram/kg initiated 10 minutes prior to PCI. All patients additionally
received ASA and a thienopyridine. The 93 enrolled NSTE-ACS patients
underwent angiography and PCI as appropriate, within 24-48 hours of
admission.
With respect to the primary endpoints of tissue level perfusion and troponin I
release, the results of EVEREST determined significantly lower rates of postPCI TMPG 0/1 (6.2% vs. 20% vs. 35.5%, respectively; p=0.015), and
improved post-PCI MCE score index (0.88 ± 0.18 vs. 0.77 ± 0.32 vs. 0.71 ±
0.30, respectively; p<0.05).
The incidence of post-procedural cardiac Troponin I (cTnI) elevation was
significantly reduced in patients treated with the upstream Aggrastat regimen
compared with PCI 25 microgram/kg dose bolus Aggrastat or abciximab
(9.4% vs. 30% vs. 38.7%, respectively; p=0.018). The cTnI levels post-PCI
were also significantly decreased with the upstream regimen of Aggrastat
compared with PCI Aggrastat (3.8 ± 4.1 vs. 7.2 ± 12; p=0.015) and abciximab
(3.8 ± 4.1 vs. 9 ± 13.8; p=0.0002). The comparison between the PCI Aggrastat
25 microgram/kg dose bolus and abciximab regimens indicated no significant
differences in the rate of TMPG 0/1 post-PCI (20% vs. 35%; p=NS).
On-Time 2 study
The On-TIME 2 trial was a multi-centre, prospective, randomised, controlled
clinical trial which was designed to assess the effect of early upfront Aggrastat

administration using the 25 microgram/kg dose bolus regimen in patients with
STEMI planned for primary PCI. All patients received ASA, a 600 mg loading
dose of clopidogrel, and unfractionated heparin. The use of bail-out Aggrastat
was allowed according to pre-specified criteria. The study was accomplished
in two phases: a pilot, open label phase (n=414) followed by a larger doubleblind phase (n=984). A pooled analysis of data from both phases was prespecified to evaluate the effect of the 25 microgram/kg dose bolus regimen
compared to control as measured by a primary endpoint defined as the 30-day
MACE rate (death, recurrent MI and uTVR).
In this pooled analysis, MACE at 30 days was significantly reduced by early
upfront initiation of Aggrastat compared to control (5.8% vs. 8.6%; p=0.043).
In addition, there was a strong trend toward a significant decrease in mortality
with Aggrastat with respect to all-cause death (2.2% in the Aggrastat arm vs.
4.1% in the control arm; p=0.051). This mortality benefit was mainly due to a
reduction of cardiac death (2.1% vs. 3.6%; p=0.086). At 1-year follow-up (the
secondary endpoint), the mortality difference was maintained (3.7% vs. 5.8%;
p=0.078 for all-cause mortality and 2.5% vs. 4.4% for cardiac mortality;
p=0.061).
Patients who underwent primary PCI (86% of study population of pooled
analysis) demonstrated a significant reduction in mortality both at 30 days
(1.0% in the Aggrastat group vs. 3.9% in the control group; p=0.001) and at 1
year (2.4% for Aggrastat vs. 5.5% for control; p=0.007).
MULTISTRATEGY study
The MULTISTRATEGY study was an open-label, 2X2 factorial,
multinational trial which compared the Aggrastat (n=372) with abciximab
(n=372) when used in conjunction with either a sirolimus-eluting (SES) or
bare metal stent (BMS), in patients with STEMI. Either Aggrastat (bolus of 25
microgram/kg, followed by an infusion at 0.15 microgram/kg/min continued
for 18 to 24 hours) or abciximab (bolus of 0.25 mg/kg, followed by a 12-hour
infusion at 0.125 microgram/kg/min) was initiated before arterial sheath
insertion during the angiography. All patients received unfractionated heparin,
ASA and clopidogrel.
The primary endpoint for the drug comparison was cumulative ST-segment
resolution expressed as the proportion of patients who achieve at least 50%
recovery within 90 minutes after the last balloon inflation and tested the
hypothesis that Aggrastat is noninferior to abciximab with respect to this
endpoint.
In the intention-to-treat population, the percentage of patients with at least
50% recovery from ST-segment elevation was not significantly different
between Aggrastat (85.3%) and abciximab (83.6%), demonstrating the noninferiority of Aggrastat to abciximab (RR for Aggrastat vs. abciximab, 1.020;
97.5% CI, 0.958-1.086; p<0.001 for non-inferiority).
At 30 days, the rates of major adverse cardiac events (MACE) were similar for
abciximab and Aggrastat (4.3% vs. 4.0%, respectively; p=0.85) with these
results maintained at 8 months (12.4% vs. 9.9%, respectively; p=0.30).

In On-TIME 2 and MULTISTRATEGY, patients were treated with dual oral
antiplatelet therapy consisting of ASA and high-dose clopidogrel. The efficacy
of Aggrastat in combination with either prasugrel or ticagrelor has not been
established in randomised controlled trials.
Meta-analysis of Randomised Trials of Aggrastat 25 microgram/kg Dose
Bolus Regimen
The results of a meta-analysis evaluating the efficacy of the Aggrastat 25
microgram/kg dose bolus regimen versus abciximab (including 2213 ACS
patients) did not reveal any significant difference in the OR for death or MI at
30 days between the two agents (OR, 0.87 [0.56-1.35]; p=0.54). Similarly,
there were no significant differences in 30-day mortality between Aggrastat
and abciximab (OR, 0.73 [0.36-1.47]; p=0.38). Additionally, at the longest
follow-up, death or MI was not significantly different between Aggrastat and
abciximab (OR, 0.84 [0.59-1.21]; p=0.35).
Target study
In one study using a 10 microgram/kg bolus followed by a 0.15
microgram/kg/min infusion of Aggrastat, Aggrastat failed to demonstrate
noninferiority to abciximab: the incidence of the composite primary endpoint
(death, MI, or uTVR at 30 days) showed that abciximab was significantly
more effective on clinically relevant endpoints, with 7.6% in the tirofiban and
6.0% in the abciximab group (p=0.038), which was mainly due to a significant
increase in the incidence of MI at 30 days (respectively 6.9% vs. 5.4%;
p=0.04).

5.2

Pharmacokinetic properties
Distribution
Tirofiban is not strongly bound to plasma protein, and protein binding is
concentration-independent in the range of 0.01–25 microgram/ml. The
unbound fraction in human plasma is 35%.
The distribution volume of tirofiban in the steady state is about 30 litres.
Biotransformation
Experiments with 14C-labelled tirofiban showed the radioactivity in urine and
faeces to be emitted chiefly by unchanged tirofiban. The radioactivity in
circulating plasma originates mainly from unchanged tirofiban (up to 10 hours
after administration). These data suggested limited metabolisation of tirofiban.
Elimination
After intravenous administration of 14C-labelled tirofiban to healthy subjects,
66% of the radioactivity was recovered in the urine, 23% in the faeces. The
total recovery of radioactivity was 91%. Renal and biliary excretion contribute
significantly to the elimination of tirofiban.
In healthy subjects the plasma clearance of tirofiban is about 250 ml/min.
Renal clearance is 39–69% of plasma clearance. The half-life is about 1.5
hours.
Gender

The plasma clearance of tirofiban in patients with coronary heart disease is
similar in men and women.
Elderly patients
The plasma clearance of tirofiban is about 25% less in elderly (>65 years)
patients with coronary heart disease in comparison to younger (≤65 years)
patients.
Ethnic groups
No difference was found in the plasma clearance between patients of different
ethnic groups.
Coronary Artery Disease
In patients with unstable angina pectoris or NQWMI the plasma clearance was
about 200 ml/min, the renal clearance 39% of the plasma clearance. The halflife is about two hours.
Impaired renal function
In clinical studies, patients with decreased renal function showed a reduced plasma
clearance of tirofiban depending on the degree of impairment of creatinine clearance.
In patients with a creatinine clearance of less than 30 ml/min, including
haemodialysis patients, the plasma clearance of tirofiban is reduced to a clinically
relevant extent (over 50%) (see section 4.2). Tirofiban is removed by haemodialysis.

Liver failure
There is no evidence of a clinically significant reduction of the plasma
clearance of tirofiban in patients with mild to moderate liver failure. No data
are available on patients with severe liver failure.
Effects of other drugs
The plasma clearance of tirofiban in patients receiving one of the following
drugs was compared to that in patients not receiving that drug in a sub-set of
patients (n=762) in the PRISM study. There were no substantial (>15%)
effects of these drugs on the plasma clearance of tirofiban: acebutolol,
alprazolam, amlodipine, aspirin preparations, atenolol, bromazepam, captopril,
diazepam, digoxin, diltiazem, docusate sodium, enalapril, furosemide,
glibenclamide, unfractionated heparin, insulin, isosorbide, lorazepam,
lovastatin, metoclopramide, metoprolol, morphine, nifedipine, nitrate
preparations, oxazepam, paracetamol, potassium chloride, propranolol,
ranitidine, simvastatin, sucralfate and temazepam.
The pharmacokinetics and pharmacodynamics of Aggrastat were investigated
when concomitantly administered with enoxaparin (1 milligram/kg
subcutaneously every 12 hours) and compared with the combination of
Aggrastat and unfractionated heparin. There was no difference in the clearance
of Aggrastat between the two groups.

5.3

Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies
of safety pharmacology, repeated dose toxicity and genotoxicity.

Fertility and reproductive performance were not affected in studies with male and
female rats given intravenous doses of tirofiban hydrochloride up to 5mg/kg/day.
These dosages are approximately 22-fold higher than the maximum recommended
daily dose in humans.
However, animal studies are insufficient to draw conclusions with respect to
reproductive toxicity in humans.
Tirofiban crosses the placenta in rats and rabbits.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium chloride, sodium citrate dihydrate, citric acid anhydrous, water for injections,
hydrochloric acid and/or sodium hydroxide (for pH adjustment).

6.2

Incompatibilities
Incompatibility has been found with diazepam. Therefore, Aggrastat and diazepam
should not be administered in the same intravenous line.
No incompatibilities have been found with Aggrastat and the following intravenous
formulations: atropine sulfate, dobutamine, dopamine, epinephrine HCl, furosemide,
heparin, lidocaine, midazolam HCl, morphine sulfate, nitroglycerin, potassium
chloride, propanolol HCl and famotidine injection.

6.3

Shelf life
3 years.

From a microbiological point of view the diluted solution for infusion should
be used immediately. If not used immediately, in use storage conditions are the
responsibility of the user and would normally not be longer than 24 hours at 28ºC, unless reconstitution has taken place in controlled and validated aseptic
conditions.

6.4

Special precautions for storage
Do not freeze. Keep container in outer carton to protect from light.
For storage conditions after dilution of the medicinal product, see section 6.3.

6.5

Nature and contents of container
50 ml Type I glass vial.

6.6

Special precautions for disposal
Aggrastat concentrate for solution for infusion must be diluted before use.

See section 4.2.
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Correvio (UK) Ltd
Lakeside House
1 Furzeground Way
Stockley Park
Heathrow
UB11 1BD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 35173/0001

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
15/07/1999

10

DATE OF REVISION OF THE TEXT
03/12/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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