Angiox 250 mg powder for concentrate for solution for injection or infusion

Each vial contains 250 mg bivalirudin.

After reconstitution 1 ml contains 50 mg bivalirudin.

After dilution 1 ml contains 5 mg bivalirudin.

For a full list of excipients see section 6.1.

Powder for concentrate for solution for injection or infusion.

White to off-white lyophilised powder.

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.

Angiox is also indicated as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI).

Angiox should be administered by a physician experienced in either acute coronary care or in coronary intervention procedures.

Posology

Patients with acute coronary syndromes (ACS)

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 of bivalirudin should be administered before the procedure 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 intravenous (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.

Patients undergoing PCI

The recommended dose of Angiox for patients undergoing PCI is an intravenous bolus of 0.75 mg/kg body weight followed immediately by an intravenous infusion at a rate of 1.75 mg/kg body weight/hour for at least the duration of the procedure. The infusion may be continued for up to 4 hours post-PCI as clinically warranted.

The safety and efficacy of a bolus only dose of Angiox has not been evaluated and is not recommended even if a short PCI procedure is planned.

The activated clotting time (ACT) may be used to assess bivalirudin activity.

In order to reduce the potential for low ACT values, the reconstituted and diluted product should be thoroughly mixed prior to administration and the bolus dose administered by a rapid intravenous push.

ACT values 5 minutes after bivalirudin bolus average 365 +/- 100 seconds. If the 5-minute ACT is less than 225 seconds, a second bolus dose of 0.3 mg/kg should be administered.

Once the ACT value is greater than 225 seconds, no further monitoring is required provided the 1.75mg/kg infusion dose is properly administered

The arterial sheath can be removed 2 hours after discontinuation of the bivalirudin infusion without further ACT monitoring.

Renal insufficiency

Angiox is contraindicated in patients with severe renal insufficiency (GFR<30ml/min) and also in dialysis-dependent patients (see section 4.3).

In patients with mild or moderate renal insufficiency, the ACS dose (0.1mg/kg bolus/0.25mg/kg/h infusion) should not be adjusted..

Patients with moderate renal impairment (GFR 30-59ml/min) undergoing PCI (whether being treated with bivalirudin for ACS or not) should receive a lower infusion rate of 1.4 mg/kg/h. The bolus dose should not be changed from the posology described under ACS or PCI above.

During PCI, monitoring of clotting time such as the ACT is recommended in patients with renal insufficiency.

The ACT should be checked at 5 minutes post bolus dose. If the ACT is less than 225 seconds, a second bolus dose of 0.3 mg/kg should be administered and the ACT re-checked 5 minutes after the administration of the second bolus dose.

Hepatic impairment

No dose adjustment is needed. Pharmacokinetic studies indicate that hepatic metabolism of bivalirudin is limited, therefore the safety and efficacy of bivalirudin have not been specifically studied in patients with hepatic impairment.

Elderly population

Caution should be exercised in the elderly due to age-related decrease in renal function.

Paediatric patients

There is no relevant indication for use of Angiox in children less than 18 years old.

Method of administration

Angiox is intended for intravenous (IV) use.

Angiox should be initially reconstituted to give a solution of 50mg/ml bivalirudin. Reconstituted material should then be further diluted in a total volume of 50ml to give a solution of 5mg/ml bivalirudin.

Reconstituted and diluted product should be thoroughly mixed prior to administration.

Refer to section 6.6 for full instructions regarding the method of administration.

Angiox is administered as a weight based regimen consisting of an initial bolus (by rapid IV push) followed by an IV infusion.

Use with low molecular weight and unfractionated heparin

Patients can be started on Angiox 30 minutes after discontinuation of unfractionated heparin given intravenously, or 8 hours after discontinuation of low molecular weight heparin given subcutaneously.

Use with GPIIb/IIIa inhibitors

Angiox can be used in conjunction with a GPIIb/IIIa inhibitor. Refer to section 5.1 for further information regarding the use of bivalirudin with or without a GPIIb/IIIa inhibitor.

Angiox is contraindicated in patients with:

• a known hypersensitivity to the active substance or to any of the excipients, or to hirudins

• active bleeding or increased risk of bleeding because of haemostasis disorders and/or irreversible coagulation disorders

• severe uncontrolled hypertension

• subacute bacterial endocarditis

• severe renal impairment (GFR<30ml/min) and in dialysis-dependent patients.

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 and 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 ( 1/1,000 to 1/100) 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 ( 1/10,000) 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.

Brachytherapy

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

Angiox should be used with caution during beta brachytherapy procedures.

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.

In any case, when bivalirudin is combined with a platelet inhibitor or an anticoagulant medicine, clinical and biological parameters of haemostasis should be regularly monitored.

Pregnancy

There are no or limited data from the use of bivalirudin in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition or post-natal development (see section 5.3).

Angiox should not be used during pregnancy unless the clinical condition of the woman requires treatment with bivalirudin.

Breastfeeding

It is unknown whether bivalirudin is excreted in human milk. Angiox should be administered with caution in breast-feeding mothers.

No studies on the effects on the ability to drive and use machines have been performed.

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 ( 1/10) and major bleeding occurred commonly (1/100 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 ( 1/10) and major bleeding occurred commonly (1/100 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.

Cases of overdose of up to 10 times the recommended dose have been reported in clinical trials. Single bolus doses of bivalirudin up to 7.5mg/kg have also been reported. None of these cases were associated with bleeding or other adverse events.

In cases of overdose, treatment with bivalirudin should be immediately discontinued and the patient monitored closely for signs of bleeding.

In the event of major bleeding, treatment with bivalirudin should be immediately discontinued. There is no known antidote to bivalirudin, however, bivalirudin is haemo-dialysable.

Pharmacotherapeutic group: Direct thrombin inhibitors, ATC code: B01AE06.

Angiox contains bivalirudin, a direct and specific thrombin inhibitor that binds both to the catalytic site and the anion-binding exosite of fluid-phase and clot-bound thrombin.

Thrombin plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework that stabilises the thrombus. Thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release. Bivalirudin inhibits each of these thrombin effects.

The binding of bivalirudin to thrombin, and therefore its activity, is reversible as thrombin slowly cleaves the bivalirudin, Arg₃-Pro₄, bond, resulting in recovery of thrombin active site function. Thus, bivalirudin initially acts as a complete non-competitive inhibitor of thrombin, but transitions over time to become a competitive inhibitor enabling initially inhibited thrombin molecules to interact with other clotting substrates and to coagulation if required.

In vitro studies have indicated that bivalirudin inhibits both soluble (free) and clot-bound thrombin. Bivalirudin remains active and is not neutralised by products of the platelet release reaction.

In vitro studies have also shown that bivalirudin prolongs the activated partial thromboplastin time (aPTT) thrombin time (TT) and pro-thrombin time (PT) of normal human plasma in a concentration-dependent manner and that bivalirudin does not induce a platelet aggregation response against sera from patients with a history of Heparin-Induced Thrombocytopenia/Thrombosis Syndrome (HIT/HITTS).

In healthy volunteers and patients, bivalirudin exhibits dose- and concentration dependent anticoagulant activity as evidenced as prolongation of the ACT, aPTT, PT, INR and TT. Intravenous administration of bivalirudin produces measurable anticoagulation within minutes.

The pharmacodynamic effects of bivalirudin may be assessed using measures of anticoagulation including the ACT. The ACT value is positively correlated with the dose and plasma concentration of bivalirudin administered. Data from 366 patients indicates that the ACT is unaffected by concomitant treatment with a GPIIb/IIIa inhibitor.

In clinical studies bivalirudin has been shown to provide adequate anticoagulation during PCI procedures.

ACUITY Trial

The ACUITY trial was a prospective, randomised open-label, trial of bivalirudin with or without GPIIb/IIIa inhibitor (Arms B and C respectively) versus unfractionated heparin or enoxaparin with GPIIb/IIIa inhibitor (Arm A) in 13,819 high risk ACS patients.

In Arms B and C of the ACUITY trial, the recommended dose of bivalirudin was an initial post-randomisation IV bolus of 0.1mg/kg followed by a continuous IV infusion of 0.25 mg/kg/h during angiography or as clinically warranted.

For patients undergoing PCI, an additional IV bolus of 0.5mg/kg bivalirudin was administered and the rate of IV infusion increased to 1.75 mg/kg/h.

In Arm A of the ACUITY trial, UFH or enoxaparin was administered in accordance with the relevant guidelines for the management of ACS in patients with UA and NSTEMI. Patients in Arms A and B were also randomised to receive a GPIIb/IIIa inhibitor either upfront at the time of randomization (prior to angiography) or at the time of PCI. A total of 356 (7.7%) of patients randomised to Arm C also received a GPIIb/IIIa inhibitor.

High risk patient characteristics of the ACUITY population that mandated angiography within 72 hours were balanced across the three treatment arms. Approximately 77% of patients had recurrent ischaemia, approximately 70% had dynamic ECG changes or elevated cardiac biomarkers, approximately 28% had diabetes and approximately 99% of patients underwent angiography within 72 hours.

Following angiographic assessment, patients were triaged to either medical management (33%), PCI (56%) or CABG (11%). Additional anti-platelet therapy utilised in the study included aspirin and clopidogrel.

The primary analysis and results for ACUITY at 30-days and 1 year for the overall (ITT) population and for the patients that received aspirin and clopidogrel as per protocol (pre-angiography or pre-PCI) are shown in Tables 3 and 4.

Table 3. ACUITY trial; 30-day and 1-year risk differences for the composite ischaemic endpoint and its components for the overall population (ITT)

Table 4. ACUITY trial; 30-day and 1-year risk differences for the composite ischaemic endpoint and its components for patients that received aspirin and clopidogrel as per protocol*

*clopidogrel pre-angiography or pre-PCI

The incidence of both ACUITY-scale and TIMI-scale bleeding events up to day 30 is presented in Table 5 for the overall (ITT) population and for patients that received aspirin and clopidogrel as per protocol.

Table 5. ACUITY trial; bleeding events up to day 30 for the overall (ITT) population and the population of patients who received aspirin and clopidogrel as per protocol*

*clopidogrel pre-angiography or pre-PCI¹

ACUITY major bleeding defined as any one of the following: intracranial, retroperitoneal, intraocular, access site haemorrhage requiring radiological or surgical intervention, 5cm diameter haematoma at puncture site, reduction in haemoglobin concentration of 4g/dl without an overt source of bleeding, reduction in haemaglobin concentration of 3g/dl with an overt source of bleeding, re-operation for bleeding, use of any blood product transfusion.

²TIMI major bleeding defined as intracranial bleeding or a decrease in haemoglobin concentration 5g/dL

The advantage of bivalirudin over UFH/enoxaparin plus GPIIb/IIIa inhibitor in terms of bleeding events was only observed in the bivalirudin monotherapy arm.

The 30-day results based on quadruple and triple endpoints from a randomized, double-blind trial of over 6,000 patients undergoing PCI (REPLACE-2), are shown in Table 6. Major bleeding in REPLACE-2 was defined by non-TIMI criteria.

Table 6. REPLACE-2 study results: 30-day endpoints (intent-to-treat and per-protocol populations

* excludes major bleeding component. **p<0.001

Heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia-thrombosis syndrome (HIT/HITTS): Clinical trials in a small number of patients have provided limited information about the use of Angiox in patients with HIT/HITTS.

The pharmacokinetic properties of bivalirudin have been evaluated and found to be linear in patients undergoing Percutaneous Coronary Intervention and in patients with ACS.

Absorption: The bioavailability of bivalirudin for intravenous use is complete and immediate. The mean steady-state concentration of bivalirudin following a constant intravenous infusion of 2.5 mg/kg/h is 12.4 µg/ml.

Distribution: Bivalirudin is rapidly distributed between plasma and extracellular fluid. The steady-state volume of distribution is 0.1 l/kg. Bivalirudin does not bind to plasma proteins (other than thrombin) or to red blood cells.

Biotransformation: As a peptide, bivalirudin is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acid in the body pool. Bivalirudin is metabolized by proteases, including thrombin. The primary metabolite resulting from the cleavage of Arg₃-Pro₄ bond of the N-terminal sequence by thrombin is not active because of the loss of affinity to the catalytic active site of thrombin. About 20% of bivalirudin is excreted unchanged in the urine.

Elimination: The concentration-time profile following intravenous administration is well described by a two-compartment model. Elimination follows a first order process with a terminal half-life of 25 ± 12 minutes in patients with normal renal function. The corresponding clearance is about 3.4 ± 0.5 ml/min/kg.

Hepatic Insufficiency: The pharmacokinetics of bivalirudin have not been studied in patients with hepatic impairment but are not expected to be altered because bivalirudin is not metabolized by liver enzymes such as cytochrome P-450 isozymes.

Renal Insufficiency: The systemic clearance of bivalirudin decreases with glomerular filtration rate (GFR). The clearance of bivalirudin is similar in patients with normal renal function and those with mild renal impairment. Clearance is reduced by approximately 20% in patients with moderate or severe renal impairment, and 80% in dialysis-dependent patients (Table 7).

Table 7. Pharmacokinetic parameters for bivalirudin in patients with normal and impaired renal function

In patients with renal insufficiency, coagulation parameters such as the ACT should be monitored during Angiox therapy.

Elderly: Pharmacokinetics have been evaluated in elderly patients as part of a renal pharmacokinetic study. Dose adjustments for this age group should be on the basis of renal function, see section 4.2.

Gender: There are no gender effects in the pharmacokinetics of bivalirudin.

Weight: Bivalirudin dose is body weight adjusted in mg/kg.

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

Toxicity in animals upon repeated or continuous exposure (1 day to 4 weeks at exposure levels of up to 10 times the clinical steady state plasma concentration) was limited to exaggerated pharmacological effects. Comparison of the single and repeated dose studies revealed that toxicity was related primarily to duration of exposure. All the undesirable effects, primary and secondary, resulting from excessive pharmacological activity were reversible. Undesirable effects that resulted from prolonged physiological stress in response to a non-homeostatic state of coagulation were not seen after short exposure comparable to that in clinical use, even at much higher doses.

Bivalirudin is intended for short-term administration and therefore no data on the long-term carcinogenic potential of bivalirudin are available. However, bivalirudin was not mutagenic or clastogenic in standard assays for such effects.

Mannitol

Sodium hydroxide solution (for pH adjustment).

The following medicinal products should not be administered in the same intravenous line as bivalirudin since they result in haze formation, micro-particulate formation or gross precipitation; alteplase, amiodarone HCl, amphotericin B, chlorpromazine HCl, diazepam, prochlorperazine edisylate, reteplase, streptokinase and vancomycin HCl.

4 years

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 28^oC.

Diluted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 25^oC.

From a microbiological point of view, the product should be used immediately. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 – 8 ^oC, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

Lyophilised powder: Do not store above 25°C.

Reconstituted solution: Store in a refrigerator (2 – 8^oC). Do not freeze.

Diluted solution: Do not store above 25°C. Do not freeze.

Angiox is supplied as a lyophilised powder in 10 ml single use glass vials (Type 1) closed with a butyl rubber stopper and sealed with a crimped aluminum seal.

Angiox is available in packs of 2 and 10 vials.

Not all pack sizes may be marketed.

Instructions for preparation

Aseptic procedures should be used for the preparation and administration of Angiox.

Add 5 ml sterile water for injections to one vial of Angiox and swirl gently until completely dissolved and the solution is clear.

Withdraw 5 ml from the vial, and further dilute in a total volume of 50 ml of glucose solution for injection 5%, or sodium chloride 9 mg/ml (0.9%) solution for injection to give a final bivalirudin concentration of 5 mg/ml.

The reconstituted/diluted solution should be inspected visually for particulate matter and discolouration. Solutions containing particulate matter should not be used.

The reconstituted/diluted solution will be a clear to slightly opalescent, colourless to slightly yellow solution.

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

The Medicines Company UK Ltd

115L Milton Park

Abingdon

Oxfordshire

OX14 4SA

UNITED KINGDOM

EU/1/04/289/001-002

20.09.2004

18.06.2009

Detailed information on this product is available on the web site of the European medicines Agency (EMEA) http://www.emea.europa.eu”