TIROFIBAN Solution for infusion Ref.[8520] Active ingredients: Tirofiban

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

There is limited experience with concomitant administration of Tirofiban with enoxaparin (see section 5.1 and section 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 bleeds**, 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 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 (>180/110 mmHg)
• 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.

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 hydrochloride 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.

Tirofiban Solution

This medicinal product contains 31 mmol (or 715 mg) sodium per bag (250 ml). To be taken into consideration by patients on a controlled sodium diet.

** 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 >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.

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 section 4.4 and section 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 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.

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 the reproductive toxicity (see section 5.3). Tirofiban is not recommended used during pregnancy unless clearly necessary.

Breastfeeding

It is not known 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 should be made whether to discontinue breastfeeding or 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 hydrochloride (see section 5.3).

However, animal studies are insufficient to draw conclusions with respect to reproductive toxicity in humans.

No data are available on whether Tirofiban impairs the ability to drive or use machines.

a. Summary of safety profile

The most common adverse reaction reported during therapy with tirofiban hydrochloride 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 hydrochloride studies were <2.2% and <0.1%, respectively. The most serious adverse reaction was fatal bleeding.

In the pivotal studies, administration of tirofiban hydrochloride 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 hydrochloride 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 1,953 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:

Blood and lymphatic system disorders

Not known: Acute and/or severe (<20,000/mm³) decreases in platelet count

Immune system disorders

Not known: Severe allergic reactions including anaphylactic reactions

Nervous system disorders

Very common: Headache

Not known: Intracranial bleeding, spinal epidural haematoma

Cardiac disorders

Not known: Hemopericardium

Vascular disorders

Very common: Haematoma

Respiratory, thoracic and mediastinal disorders

Common: Haemoptysis, epistaxis

Not known: Pulmonary (alveolar) haemorrhage

Gastrointestinal disorders

Very common: Nausea

Common: Oral haemorrhage, gingival haemorrhage

Uncommon: GI haemorrhage, haematemesis

Not known: Retroperitoneal bleeding

Skin and subcutaneous disorders

Very common: Ecchymosis

Renal and urinary disorders

Common: Haematuria

General disorders and administration site conditions

Common: Fever

Injury, poisoning and procedural complications

Very common: Post-operative haemorrhage*

Common: Vessel puncture site haemorrhage

Investigations

Very common: Occult blood in stool or urine

Common: Decrease in haematocrit and haemoglobin, platelet count <90,000/mm³

Uncommon: Platelet counts <50,000/mm³

* Primarily related to catheterisation 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, therapy 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 re-administration 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 (website: www.mhra.gov.uk/yellowcard).

Incompatibility has been found with diazepam. Therefore, Tirofiban and diazepam should not be administered in the same intravenous line.

No incompatibilities have been found with tirofiban and the following intravenous formulations: atropine sulphate, dobutamine, dopamine, epinephrine HCl, furosemide, heparin, lidocaine, midazolam HCl, morphine sulphate, nitroglycerin, potassium chloride, propanolol HCl and famotidine injection.