SYNER-KINASE Powder for solution for injection or infusion Ref.[9391] Active ingredients: Urokinase

In the following conditions the risk of bleeding may be increased and should be weighed against the anticipated benefits of treatment with urokinase:

• Recent surgery
• Severe cerebrovascular disease
• Moderate coagulation defects including those due to severe renal or hepatic disease
• High likelihood of a left heart thrombus (e.g. mitral stenosis with atrial fibrillation) with possible risk of cerebral embolism
• Cavernous pulmonary diseases
• Genitourinary tract diseases with existing or potential sources of bleeding (e.g. implanted bladder catheter)
• Known septic thrombotic disease
• Elderly patients, especially those over 75 years of age

When bleeding occurs in patients receiving urokinase, it may be difficult to control. Although urokinase is intended to produce sufficient amounts of plasmin to lyse intravascular deposits of fibrin, other fibrin deposits including those which provide haemostasis (at sites of needle puncture, catheter insertion, cut, etc.) are also subject to lysis, and bleeding from such sites may result. Oozing of blood from sites of percutaneous trauma occurs frequently.

The possibility of bruising or haematoma formation, especially after intramuscular injections, is high during urokinase therapy. Intramuscular injections and unnecessary handling of the patient should be avoided. Venipuctures and invasive venous procedures should be performed as infrequently as possible and with care to minimise bleeding. If bleeding from an invasive site is not serious, urokinase therapy may be continued while closely observing the patient; local measures such as application of pressure should be initiated immediately.

Arterial invasive procedures must be avoided before and during urokinase treatment to minimise bleeding. If an arterial puncture is absolutely essential, it should be performed by a physician experienced in the procedure, using a radial or brachial rather than a femoral artery. Direct pressure should be applied at the puncture site for at least 30 minutes, a pressure dressing applied, and the site checked frequently for evidence of bleeding.

If severe bleeding occurs during systemic treatment with Syner-KINASE, treatment should be stopped immediately and measures to manage the bleeding implemented (see section 4.9).

Concomitant administration of urokinase with other thrombolytics, anticoagulants or anti-platelet agents may increase the risk of bleeding (see section 4.5).

Concomitant administration of urokinase with angiotensin converting enzyme (ACE) inhibitors, may increase the risk of angioedema (see section 4.5)

Syner-KINASE contains highly purified urokinase which is obtained from human urine. Products manufactured from human source materials have the potential to transmit infectious agents. Procedures to control such risks strongly reduce but cannot completely eliminate the risk of transmitting infectious agents.

Therapeutic monitoring

Before thrombolytic therapy the following laboratory tests are indicated: thrombin time (TT), activated partial thromboplastin time (aPTT), prothrombin time (PT), haematocrit and platelet count. If heparin has been given it should be discontinued (unless the patient is receiving haemodialysis) and the TT or aPTT should be less than twice the normal control value before thrombolytic therapy is started.

Therapeutic monitoring should consist of circulating fibrinogen levels and fibrinogen degradation products. However, these tests do not reliably predict efficacy and bleeding complications.

After fibrinolytic therapy has been completed, suitable anticoagulant therapy should be considered provided that the TT or aPTT is less than twice the normal control value.

Loss of activity of urokinase has been noted when dissolved in 5% glucose at a concentration of 1,500 IU/ml and stored in PVC containers (see section 6.2). No information is available regarding other dilutions of urokinase.

Anticoagulants

Concurrent administration of oral anticoagulants or heparin may increase the risk of haemorrhage.

Medicinal products affecting platelet function

Concurrent administration of substances that affect platelet function (e.g. acetylsalicylic acid, clopidogrel, other non-steroidal anti-inflammatory agents, dipyridamole, dextrans) may increase the risk of haemorrhage

Angiotensin converting enzyme (ACE) inhibitors

These agents are able to inhibit the breakdown of bradykinin that can be generated through the fibrinolysis pathway. Therefore, concomitant administration of urokinase with ACE inhibitors may increase the risk of angioedema.

Contrast agents

Contrast agents may delay fibrinolysis.

Pregnancy

There is a limited amount of data from the use of urokinase in pregnant women. Syner-KINASE should not be given during pregnancy or in the immediate post-partum period unless clearly necessary.

Breast-feeding

It is unknown whether urokinase is excreted into human breast milk. Breast-feeding should be avoided during treatment with Syner-KINASE.

Fertility

No human data on the effect of urokinase on fertility are available.

Not relevant.

There are limited data available on the adverse effects of urokinase from controlled clinical trials. The adverse reactions described below reflect the available data from these clinical trials and the clinical use of urokinase in the general population, where it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure.

Haemorrhage:

The most frequent and severe adverse effect of urokinase therapy is haemorrhage. Severe spontaneous bleeding, including fatalities resulting from cerebral haemorrhage, has occurred during urokinase therapy. Less severe spontaneous bleeding has occurred approximately twice as frequently as that occurring during heparin therapy. Patients with pre-existing haemostatic defects have the greatest risk of spontaneous bleeding.

Moderate decreases in haematocrit not accompanied by clinically detectable bleeding have been reported in approximately 20% of patients receiving urokinase.

Embolism:

Embolic episodes may occur after fragments of clot have been released. Cholesterol embolisms have also been reported.

Hypersensitivity reactions:

Urokinase is reportedly non-antigenic but mild hypersensitivity reactions including urticaria, rash, bronchospasm and very rare cases of fatal anaphylaxis have been reported.

Infusion reactions:

Infusion reactions including fever and shaking chills (rigors) have been reported. Symptomatic treatment is usually sufficient to alleviate discomfort caused by urokinase-induced fever, however, acetylsalicylic acid should not be used.

Other infusion reactions include dyspnoea, cyanosis, hypoxemia, acidosis, back pain, and nausea and/or vomiting; these reactions generally occurred within one hour of beginning urokinase infusion.

The following frequency convention was used as a basis for the evaluation of undesirable effects: 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).

Immune system disorders

Rare: Hypersensitivity reactions, including urticaria, dyspnoea, hypotension, flushing, rash

Very rare: Anaphylaxis

Nervous system disorders

Common: Stroke

Vascular disorders

Very common: Haemorrhage, including from puncture site and wound, Epistaxis, gingival bleeding, Thromboembolism, Embolism, including pulmonary embolism, Haematuria (microscopic)

Common: Gastrointestinal haemorrhage, intracranial haemorrhage, retroperitoneal haemorrhage, urogenital haemorrhage, muscle haemorrhage, Artery dissection, Cholesterol embolism

Uncommon: Intrahepatic haemorrhage

Rare: Vascular pseudoaneurysm, Haematuria (macroscopic)

Renal and urinary disorders

Uncommon: Renal failure

General disorders and administration site conditions

Common: Fever, chills

Investigations

Very common: Decrease in haematocrit without clinically detectable haemorrhage, Transient increase in transaminases

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

Syner-KINASE should be reconstituted before use only with the solvent described in Section 6.6. It has been reported to lose 15-20% of its activity in solutions of 5% glucose containing 1,500 units/ml in PVC containers. No information is available regarding other dilutions of urokinase.

Syner-KINASE must not be mixed with other medicinal products.