4.1. Therapeutic indications

Tirofiban 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 Tirofiban 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). Tirofiban 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).

Tirofiban 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.

Tirofiban 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, tirofiban is given intravenously at an initial infusion rate of 0.4 microgram/kg/min for 30 minutes. At the end of the initial infusion, tirofiban should be continued at a maintenance infusion rate of 0.1 microgram/kg/min. Tirofiban should be given with unfractionated heparin (usually an intravenous bolus of 50-60 units [U]/kg simultaneously with the start of tirofiban 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, Tirofiban should be administered utilising 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. Tirofiban 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 <30 ml/min) the dosage of Tirofiban should be reduced by 50% (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Tirofiban 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.

Table 1: Dosing Table

0.4 microgram/kg/min Loading Dose Regimen

Most Patients

0.4 microgram/kg/min Loading Dose Regimen

Severe Kidney Failure

25 microgram/kg Dose Bolus Regimen

Most Patients

25 microgram/kg Dose Bolus Regimen

Severe Kidney Failure

Patient Weight (kg)

30 min Loading

Infusion Rate

(ml/hr)

Maintenance Infusion Rate

(ml/hr)

30 min Loading

Infusion Rate

(ml/hr)

Maintenance Infusion Rate

(ml/hr)

Bolus

(ml)

Maintenance Infusion Rate

(ml/hr)

Bolus

(ml)

Maintenance Infusion Rate

(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

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 Tirofiban

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, Tirofiban 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 Tirofiban 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 tirofiban 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 Tirofiban (see section 5.1). This medication should be continued at least for the duration of the infusion of Tirofiban.

Most studies investigating the administration of Tirofiban as an adjunct to PCI have used ASA in combination with clopidogrel as oral antiplatelet therapy. The efficacy of the combination of Tirofiban 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

Check the expiry date.

Do not withdraw solution directly from the container with a syringe.

Do not use unless solution is clear and bag is intact.

Do not add supplementary medication or withdraw solution directly from the bag with a syringe.

CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.

Preparation for administration

1. Suspend container from eyelet support

2. Remove plastic protector from outlet port at bottom of container

3. Attach administration set. Refer to complete directions accompanying set

Use according to the dosage table above

Where the solution and container permit, parenteral drugs should be inspected for visible particles or discoloration before use.

Tirofiban should only be given intravenously and may be administered with unfractionated heparin through the same infusion tube.

It is recommended that Tirofiban 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

Tirofiban 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, Tirofiban 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

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

• Severe liver failure

4.4. Special warnings and precautions for use

The administration of Tirofiban alone without unfractionated heparin is not recommended.

There is limited experience with concomitant administration of Tirofiban with enoxaparin (see sections 5.1 and 5.2). The concomitant administration of Tirofiban with enoxaparin is associated with a higher frequency of cutaneous and oral bleeding events, but not in TIMI bleeds1, when compared with the concomitant administration of Tirofiban and unfractionated heparin. An increased risk of serious bleeding events associated with the concomitant administration of Tirofiban and enoxaparin cannot be excluded, particularly in patients given additional unfractionated heparin in conjunction with angiography and/or PCI. The efficacy of Tirofiban in combination with enoxaparin has not been established. The safety and efficacy of Tirofiban with other low molecular weight heparins has not been investigated.

There is insufficient experience with the use of tirofiban in the following diseases and conditions, however, an increased risk of bleeding is suspected. Therefore, tirofiban 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 (>180/110 mm Hg)

• 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 in patients for whom thrombolytic therapy is indicated. Consequently, the use of tirofiban is not recommended in combination with thrombolytic therapy.

Tirofiban 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

There is no therapeutic experience with Tirofiban in children, thus, the use of Tirofiban is not recommended in these patients.

Other precautionary notes and measures

There are insufficient data regarding the re-administration of Tirofiban.

Patients should be carefully monitored for bleeding during treatment with Tirofiban. If treatment of haemorrhage is necessary, discontinuation of Tirofiban should be considered (see section 4.9). In cases of major or uncontrollable bleeding, tirofiban should be discontinued immediately.

Tirofiban 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 Tirofiban

• 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 Tirofiban 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 Tirofiban and the heparin effect should be carefully monitored. In severe kidney failure the Tirofiban dosage should be reduced (see section 4.2).

Femoral artery line

During treatment with Tirofiban 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 Tirofiban. 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 Tirofiban as well as within 2-6 hours after start of therapy with Tirofiban 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, Tirofiban 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

This medicinal product contains 916.28 mg sodium per 250 ml bag, equivalent to 46% of the WHO recommended maximum daily intake of 2g sodium for an adult.

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

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 Tirofiban and ASA increases the inhibition of platelet aggregation to a greater extent than ASA alone, as measured by ex vivo APD-induced platelet aggregation test. The concomitant administration of Tirofiban 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 Tirofiban, 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).

Tirofiban prolonged bleeding time; however, the combined administration of Tirofiban and ticlopidine did not additionally affect bleeding time.

Concomitant use of warfarin with Tirofiban plus heparin was associated with an increased risk of bleeding.

Tirofiban is not recommended in thrombolytic therapy - concurrent or less than 48 hours before administration of tirofiban 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 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 in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Tirofiban is not recommended during pregnancy unless clearly necessary.

Breast-feeding

It is not known whether Tirofiban is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of tirofiban in milk (for details see section 5.3). A risk to the newborn cannot be excluded. A decision should be made whether to discontinue breastfeeding or to discontinue Tirofiban 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 (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 Tirofiban, 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 post-operative 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 Tirofiban studies were ≤2.2% and <0.1%, respectively. The most serious adverse reaction was fatal bleeding.

In the pivotal studies, administration of Tirofiban was associated with thrombocytopenia (platelet count <90,000/mm3), occurring in 1.5% of patients treated with Tirofiban 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 Tirofiban 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 Tirofiban 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

Hemopericardium

Vascular disorders

Haematoma

Respiratory, thoracic and mediastinal disorders

Haemoptysis, epistaxis

Pulmonary (alveolar) haemorrhage

Gastrointestinal disorders

Nausea

Oral haemorrhage gingival haemorrhage

GI haemorrhage, haematemesis

Retroperitoneal bleeding

Skin and subcutaneous tissue disorders

Ecchymosis

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

platelet counts <50,000/ mm3

*Primarily related to catheterization sites.

c. Description of selected adverse reactions

Bleeding

Both with the Tirofiban 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 Tirofiban 0.4 microgram/kg/min infusion regimen, the incidence of TIMI major bleeding was 1.4% for Tirofiban in combination with heparin and 0.8% for heparin alone. The incidence of TIMI minor bleeding was 10.5% for Tirofiban in combination with heparin and 8.0% for heparin alone. The percentage of patients who received a transfusion was 4.0% for Tirofiban in combination with heparin and 2.8% for heparin alone.

With the Tirofiban 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 Tirofiban 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 Tirofiban 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 Tirofiban 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 Tirofiban 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 Tirofiban 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 Tirofiban therapy, acute decreases in platelet count or thrombocytopenia occurred more frequently than in the placebo group. These decreases were reversible upon discontinuation of Tirofiban. 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 Tirofiban (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 Tirofiban. 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Inadvertent overdose with tirofiban 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 should be treated in accordance with the patient's condition and the attending physician's assessment. If treatment of haemorrhage is necessary, the Tirofiban infusion should be discontinued. Transfusions of blood and/or thrombocytes should also be considered. Tirofiban can be removed by haemodialysis.