The Medicines Company

4.8     Undesirable effects

The ACUITY Trial (ACS)

The following adverse reaction data are based on a clinical study of bivalirudin in 13,819 patients with ACS; 4,612 were randomised to bivalirudin alone, 4,604 were randomised to bivalirudin plus GPIIb/IIIa inhibitor and 4,603 were randomised to either unfractionated heparin or enoxaparin plus GPIIb/IIIa inhibitor. Adverse reactions were more frequent in females and in patients more than 65 years of age in both the bivalirudin and the heparin-treated comparator groups compared to male or younger patients.

Approximately 23.3% of patients receiving bivalirudin experienced at least one adverse event and 2.1% experienced an adverse reaction. Adverse event reactions are listed by system organ class in Table 1.

Platelets, bleeding and clotting

In ACUITY, bleeding data were collected separately from adverse reactions.

ACUITY major bleeding was defined as any one of the following: intracranial, retroperitoneal, intraocular, access site haemorrhage requiring radiological or surgical intervention, ≥5 cm diameter haematoma at puncture site, reduction in haemoglobin concentration of  ≥4 g/dl without an overt source of bleeding, reduction in haemoglobin concentration of ≥3 g/dl with an overt source of bleeding, re-operation for bleeding or use of any blood product transfusion. Minor bleeding was defined as any observed bleeding event that did not meet the criteria as major. Minor bleeding occurred very commonly (³ 1/10) and major bleeding occurred commonly (³1/100 and <1/10).

Major bleeding rates are shown in Table 5. Both major and minor bleeds were significantly less frequent with bivalirudin alone than the heparin plus GPIIb/IIIa inhibitor and bivalirudin plus GPIIb/IIIa inhibitor groups. Similar reductions in bleeding were observed in patients who were switched to bivalirudin from heparin-based therapies (N = 2,078).

Major bleeding occurred most frequently at the sheath puncture site. Other less frequently observed bleeding sites with greater than 0.1% (uncommon) bleeding included “other” puncture site, retroperitoneal, gastrointestinal, ear, nose or throat.

Thrombocytopenia was reported in 10 bivalirudin-treated patients participating in the ACUITY study (0.1%). The majority of these patients received concomitant acetylsalicylic acid and clopidogrel, and 6 out of the 10 patients also received a GPIIb/IIIa inhibitor. Mortality among these patients was nil.

Table 1.           ACUITY trial; adverse reaction data

¹ This reaction has also been seen in post-marketing exposure

The REPLACE-2 Trial (PCI)

The following adverse reaction data is based on a clinical study of bivalirudin in 6000 patients undergoing PCI, half of whom were treated with bivalirudin (REPLACE-2). Adverse events were more frequent in females and in patients more than 65 years of age in both the bivalirudin and the heparin-treated comparator groups compared to male or younger patients.

Approximately 30% of patients receiving bivalirudin experienced at least one adverse event and 3% experienced an adverse reaction. Adverse reactions are listed by system organ class in Table 2.

Platelets, bleeding and clotting

In REPLACE-2, bleeding data were collected separately from adverse events. Major bleeding rates for the intent to treat and per protocol trial populations are shown in Table 6.

Major bleeding was defined as the occurrence of any of the following: intracranial haemorrhage, retroperitoneal haemorrhage, blood loss leading to a transfusion of at least two units of whole blood or packed red blood cells, or bleeding resulting in a haemoglobin drop of more than 3 g/dl, or a fall in haemoglobin greater than 4 g/dl (or 12% of haematocrit) with no bleeding site identified. Minor haemorrhage was defined as any observed bleeding event that did not meet the criteria for a major haemorrhage. Minor bleeding occurred very commonly (³ 1/10) and major bleeding occurred commonly (³1/100 and <1/10).

Both minor and major bleeds were significantly less frequent with bivalirudin than the heparin plus GPIIb/IIIa inhibitor comparator group. Major bleeding occurred most frequently at the sheath puncture site. Other less frequently observed bleeding sites with greater than 0.1% (uncommon) bleeding included “other” puncture site, retroperitoneal, gastrointestinal, ear, nose or throat.

Table 2.  REPLACE-2 trial; adverse reaction data

¹ This reaction has also been seen in post-marketing exposure

Post-marketing experience

The following events have been reported in post-marketing experience with bivalirudin, and are described in the tables above:

·    Serious bleeding, including haematoma and bleeding with a fatal outcome

·    Intracranial haemorrhage

·    Thrombosis formation, including reports with a fatal outcome

·    Hypersensitivity, including urticaria, anaphylactic reaction, anaphylactic shock, and fatal shock.

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4.4     Special warnings and precautions for use

Angiox is not intended for intramuscular use.  Do not administer intramuscularly.

Haemorrhage: Patients must be observed carefully for symptoms and signs of bleeding during treatment particularly if bivalirudin is combined with another anticoagulant (see section 4.5).  Although most bleeding associated with bivalirudin occurs at the site of arterial puncture in patients undergoing PCI, haemorrhage can occur at any site during therapy.  Unexplained decreases in haematocrit, haemoglobin or blood pressure may indicate haemorrhage.  Treatment should be stopped if bleeding is observed or suspected.

There is no known antidote to bivalirudin but its effect wears off quickly (T½ is 35 to 40 minutes).

Co-administration with platelet inhibitors or anti-coagulants: Combined use of anti-coagulant medicines can be expected to increase the risk of bleeding (see section 4.5).  When bivalirudin is combined with a platelet inhibitor or an anti-coagulant medicine, clinical andor biological parameters of haemostatsis should be regularly monitored.

In patients taking warfarin who are treated with bivalirudin, International Normalised Ratio (INR) monitoring should be considered to ensure that it returns to pre-treatment levels following discontinuation of bivalirudin treatment.

Hypersensitivity: Allergic type hypersensitivity reactions were reported uncommonly in clinical trials.  Necessary preparations should be made to deal with this. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of chest, wheezing, hypotension and anaphylaxis.  In the case of shock, the current medical standards for shock treatment should be applied.  Anaphylaxis, including anaphylactic shock with fatal outcome has been reported very rarely in post-marketing experience (see section 4.8).

Treatment-emergent positive bivalirudin antibodies are rare and have not been associated with clinical evidence of allergic or anaphylactic reactions.  Caution should be exercised in patients previously treated with lepirudin who had developed lepirudin antibodies.

Intra-procedural thrombus formation has been observed during gamma brachytherapy procedures with Angiox.

Angiox should be used with caution during beta brachytherapy procedures.

4.5     Interaction with other medicinal products and other forms of interaction

Drug-drug interaction studies have been conducted with platelet inhibitors, including acetylsalicylic acid, ticlopidine, clopidogrel, abciximab, eptifibatide, or tirofiban.  The results do not suggest pharmacodynamic interactions with these medicinal products.

From the knowledge of their mechanism of action, combined use of anti-coagulant medicinal products (heparin, warfarin, thrombolytics or antiplatelet agents) can be expected to increase the risk of bleeding.

Post-marketing experience

Adverse reactions that have been reported from extensive post-marketing experience (approximately 1,200,000 patients exposed) and that have not been reported above are summarised by system organ class in Table 6. 

Serious bleeding, including bleeding with a fatal outcome has been reported in post-marketing experience for bivalirudin.

The licence indication has been expanded from anticoagulation during PCI to:
"For the treatment of adult patients with acute coronary syndromes (unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI)) planned for urgent or early intervention.  Angiox should be administered with aspirin and clopidogrel.
 
An anticoagulant in patients undergoing percutaneous coronary intervention (PCI)."

The recommended starting dose of Angiox for patients with ACS is an intravenous bolus of 0.1 mg/kg followed by an infusion of 0.25 mg/kg/h.  Patients who are to be medically managed may continue the infusion of 0.25 mg/kg/h for up to 72 hours.

If the patient proceeds to PCI, an additional bolus of 0.5 mg/kg should be administered and the infusion increased to 1.75 mg/kg/h for the duration of the procedure.

Following PCI, the reduced infusion dose of 0.25 mg/kg/h may be resumed for 4 to 12 hours as clinically necessary.

For patients who proceed to coronary artery bypass graft (CABG) surgery off pump, the IV infusion of bivalirudin should be continued until the time of surgery. Just prior to surgery, a 0.5mg/kg bolus dose should be administered followed by a 1.75mg/kg/h infusion for the duration of the surgery.

For patients who proceed to CABG surgery on pump, the IV infusion of bivalirudin should be continued until 1 hour prior to surgery after which the infusion should be discontinued and the patient treated with unfractionated heparin.

Section 6.5: Nature and contents of container - 2 vial pack and the sentence 'Not all pack sizes may be marketed' added

Section 8: Marketing Authorisation Number - updated with '002' at the end of the number as this is the licence number for the 2 vial pack

Section 10: Date of the revision of the text - 6th September 2006 added

* Some minor formatting changes to the Word document.