Bivalirudin Cipla 250 mg Pulver till koncentrat till injektions-/infusionsvätska, lösning

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

19-02-2019

Produktens egenskaper Produktens egenskaper (SPC)

31-03-2020

Aktiva substanser:
bivalirudin
Tillgänglig från:
Cipla Europe NV,
ATC-kod:
B01AE06
INN (International namn):
bivalirudin
Dos:
250 mg
Läkemedelsform:
Pulver till koncentrat till injektions-/infusionsvätska, lösning
Sammansättning:
bivalirudin 250 mg Aktiv substans; mannitol Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Injektionsflaska, 1 st; Injektionsflaska, 10 x 1 st
Bemyndigande status:
Avregistrerad
Godkännandenummer:
51906
Tillstånd datum:
2016-08-24

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

31-03-2020

Produktens egenskaper Produktens egenskaper - engelska

31-03-2020

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

01-11-2016

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Package leaflet: Information for the user

Bivalirudin Cipla 250 mg powder for concentrate for solution for injection/ infusion

bivalirudin

Read all of this leaflet carefully before you start using this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor.

If you get any side effects talk to your doctor. This includes any possible side effects not listed in

this leaflet. See section 4.

What is in this leaflet

1. What Bivalirudin Cipla is and what it is used for

2. What you need to know before you use Bivalirudin Cipla

3. How to use Bivalirudin Cipla

4. Possible side effects

5. How to store Bivalirudin Cipla

6. Contents of the pack and other information

1.

What Bivalirudin Cipla is and what it is used for

Bivalirudin Cipla contains a substance called bivalirudin which is an antithrombotic medicine.

Antithrombotics are medicines which prevent the formation of blood clots (thrombosis).

Bivalirudin Cipla is used to treat patients

:

with chest pain due to heart disease (acute coronary syndromes - ACS);

who are having surgery to treat blockages in their blood vessels (angioplasty and/or

percutaneous coronary intervention - PCI).

2.

What you need to know before you use Bivalirudin Cipla

Do not use Bivalirudin Cipla

if you are allergic to bivalirudin or any of the other ingredients of this medicine (listed in

section 6) or hirudins (other blood thinning medicines);

if you have, or have recently had, any bleeding from your stomach, intestines, bladder or other

organs, for example, if you have noticed abnormal blood in your stools or urine (except from

menstrual bleeding);

if you have, or have had, difficulty with your blood clotting (a low platelet count);

if you have severe high blood pressure;

if you have an infection of the heart tissue;

if you have severe kidney problems or if you need kidney dialysis.

Check with the doctor if you are not sure.

Warnings and precautions

Talk to your doctor before using Bivalirudin Cipla

if bleeding occurs (if this happens, treatment with Bivalirudin Cipla will be stopped).

Throughout your treatment, the doctor will check you for any signs of bleeding;

if you have been treated before with medicines similar to Bivalirudin Cipla (e.g. lepirudin);

before the start of the injection or infusion, the doctor will tell you about the signs of allergic

reaction. Such a reaction is uncommon (may affect up to 1 in 100 people);

if you are having radiation treatment in the vessels that supply blood to the heart (treatment

called beta or gamma brachytherapy).

After being treated with Bivalirudin Cipla for a cardiac event, you should stay in the hospital for at

least 24 hours and you should be monitored for any symptoms or signs similar to the ones that

remind you of your cardiac event and resulted in your hospitalisation.

Children and adolescents

if you are a child (less than 18 years of age), this medicine is not appropriate for you.

Other medicines and Bivalirudin Cipla

Tell your doctor

if you are taking, or have recently taken or might take any other medicines;

If you are taking blood thinners or medicines to prevent blood clots (anticoagulants or

antithrombotics e.g. warfarin, dabigatran, apixaban, rivaroxaban, acetylsalicylic acid,

clopidogrel, prasugrel, ticagrelor).

These medicines may increase the risk of side effects such as bleeding when given at the same

time as Bivalirudin Cipla. Your warfarin blood test result (INR test) may be affected by

Bivalirudin Cipla.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby,

ask your doctor for advice before taking this medicine.

Bivalirudin Cipla should not be used during pregnancy, unless clearly necessary. Your doctor will

decide whether or not this treatment is appropriate for you. If you are breast-feeding, the doctor

will decide whether Bivalirudin Cipla should be used.

Driving and using machines

The effects of this medicine are known to be short-term. Bivalirudin Cipla is only given when a

patient is in hospital. It is, therefore, unlikely to affect your ability to drive or to use machines.

Bivalirudin Cipla contains sodium

This medicine contains less than 23 mg of sodium per vial, which means that it is essentially

“sodium-free”.

3.

How to use Bivalirudin Cipla

Your treatment with Bivalirudin Cipla will be supervised by a doctor. The doctor will decide how

much Bivalirudin Cipla you receive, and will prepare the medicine.

The dose given depends on your weight and on the kind of treatment you are being given.

Dosage

For patients with acute coronary syndromes (ACS) who are treated medically

recommended

starting dose

0.1 mg/kg body weight as an intravenous injection, followed by an infusion (drip) into vein of

0.25 mg/kg body weight per hour for up to 72 hours.

If, after this,

you

then need percutaneous coronary intervention (PCI) treatment, the dosage will be

increased to:

0.5 mg/kg body weight for the intravenous injection, followed by an infusion into vein of 1.75

mg/kg body weight, per hour for the duration of the PCI.

When this treatment is finished, the infusion may go back to

0.25 mg/kg

body weight per hour

for an additional 4 to 12 hours.

If you need to have a coronary artery bypass graft operation, treatment with bivalirudin will either

be stopped one hour before the operation or an additional dose of 0.5 mg/kg body weight will be

given by injection followed by an infusion of 1.75 mg/kg body weight per hour for the duration of

surgery.

For patients starting with percutaneous coronary intervention (PCI)

the recommended

dose

0.75 mg/kg

body weight as an intravenous injection, followed immediately by an infusion

(drip) into vein of

1.75 mg/kg

body weight, per hour for at least the duration of the PCI. The

intravenous infusion may continue at this dose for up to 4 hours after the PCI and for STEMI

patients (those with a severe type of heart attack) it should continue at this dose for up to 4

hours. The infusion may be followed by an infusion at a lower dose of 0.25 mg/kg body

weight for an additional 4 to 12 hours.

If you have kidney problems, the dose of Bivalirudin Cipla may need to be reduced.

In the elderly, if their kidney function is decreased, the dose may need to be reduced.

The doctor will decide for how long you should be treated.

Bivalirudin Cipla is for injection, followed by infusion (drip), into a vein (never into a muscle).

This is administered and supervised by a doctor experienced in caring for patients with heart

disease.

If you receive more Bivalirudin Cipla than you should

Your doctor will decide how to treat you, including stopping the drug and monitoring for signs of

ill effects.

If you have any further questions on the use of this medicine, ask your doctor.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you get any of the following, potentially serious, side effects:

while you are in hospital: tell the doctor or nurse immediately;

after you’ve left hospital: contact your doctor directly or go immediately to the

Emergency Department of your nearest hospital.

The most common, (may affect up to 1 in 10 people) serious side effect of treatment with

bivalirudin, is major bleeding which could occur anywhere inside the body (e.g. stomach, digestive

system (including vomiting blood or passing blood with the stools), abdomen, lungs, groin,

bladder, heart, eye, ear, nose or brain). This may,

rarely

, result in a stroke or be fatal. Swelling or

pain in the groin or the arm, back pain, bruising, headache, coughing blood, pink or red urine,

sweating, feeling faint or sick or dizzy due to low blood pressure may be signs of internal

bleeding. Bleeding is more likely to occur when Bivalirudin is used in combination with other

anticoagulant or antithrombotic medicines (see section 2 ‘Other medicines and Bivalirudin Cipla).

Bleeding and bruising at the puncture site (after PCI treatment) may be painful. Rarely this may

require surgery to repair the blood vessel in the groin (fistula, pseudoaneurysm) (may affect up

to 1 in 1,000 people). Uncommonly (may affect up to 1 in 100 people) the number of blood

platelets may be low which can worsen any bleeding. Gum bleeding (uncommon, may affect up

to 1 in 100 people) is usually not serious.

Allergic reactions,- are uncommon (may affect up to 1 in 100 people) and usually not serious

but can become severe under some circumstances, and in rare cases may be fatal due to low

blood pressure (shock). They may begin with limited symptoms such as itching, redness of the

skin, rash or small bumps on the skin. Occasionally, reactions can be more severe with throat

itching, throat tightening, swelling of the eyes, face, tongue or lips, high pitched whistling

during inhaling (stridor), difficulty breathing or exhaling (wheezes).

Thrombosis (blood clot) is an uncommon side effect (may affect up to 1 in 100 people) which

may result in serious or fatal complications such as heart attack. Thrombosis includes coronary

artery thrombosis (blood clot in the heart arteries or within a stent being felt as a heart attack

which can also be fatal) and/or thrombosis in the catheter, both of which are rare (may affect up

to 1 in 1,000 people).

If you get any of the following, (potentially less serious), side effects:

while you are in hospital: tell the doctor or nurse;

after you’ve left hospital: first seek advice from your doctor. If you cannot get access to

your doctor go immediately to the Emergency Department of your nearest hospital.

Very common side effects (may affect more than 1 in 10 people):

minor bleeding.

Common side effects (may affect up to 1 in 10 people):

anaemia (a low blood cell count);

haematoma (bruising).

Uncommon side effects (may affect up to 1 in 100 people):

nausea (feeling sick) and/or vomiting (being sick).

Rare side effects (may affect up to 1 in 1000 people)

INR test (warfarin blood test result) increased (see Section 2, Other medicines and Bivalirudin);

angina or chest pain;

slow heartbeat;

rapid heartbeat;

shortness of breath;

reperfusion injury (no or slow reflow): impaired flow in the heart arteries after they have been

reopened.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via national reporting

system listed in Appendix V*. By reporting side effects you can help provide more information on

the safety of this medicine

5.

How to store Bivalirudin Cipla

As Bivalirudin Cipla is a hospital only medicine, storage of Bivalirudin Cipla is the responsibility

of healthcare professionals.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after ‘EXP’.

The expiry date refers to the last day of that month.

This medicinal product does not require any specific storage condition.

Reconstituted solution

:

Chemical and physical in-use stability has been demonstrated for 24 hours

at 2–8°C. Store in a refrigerator (2–8°C). Do not freeze.

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

25°C and at 2–8°C. Do not store above 25°C. Do not freeze.

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°C unless reconstitution/dilution has taken place

in controlled and validated aseptic conditions.

The solution should be a clear colourless solution, without any visible extraneous matter.

The doctor will check the solution and will discard it, if it contains particles or is discoloured.

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away

medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Bivalirudin Cipla contains

The active substance is bivalirudin. Each vial contains 250 mg bivalirudin. After reconstitution

1 ml contains 50 mg bivalirudin. After dilution 1 ml contains 5 mg bivalirudin.

The other ingredients are mannitol and sodium hydroxide.

What Bivalirudin Cipla looks like and contents of the pack

Bivalirudin Cipla is a white to off-white lyophilised powder/cake supplied in 10 ml vials (Type 1

glass) with stopper (butyl rubber) with seal (aluminum), containing 250 mg bivalirudin.

Pack sizes: 1 and 10 vials.

Not all pack sizes may be marketed

This medicinal product is authorised in the Member States of the EEA under the following

names:

<To be completed nationally>

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

<To be completed nationally>

Manufacturer

<To be completed nationally>

This leaflet was last revised in 2020-03-26

---------------------------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

Healthcare professionals should refer to the Summary of Product Characteristics for full prescribing

information.

Bivalirudin Cipla is indicated as an anticoagulant in adult patients undergoing percutaneous coronary

intervention (PCI), including patients with ST-segment elevation myocardial infarction (STEMI)

undergoing primary PCI.

Bivalirudin Cipla is also indicated for the treatment of adult patients with unstable angina/non-ST

segment elevation myocardial infarction (UA/NSTEMI) planned for urgent or early intervention.

Bivalirudin should be administered with acetylsalicylic acid and clopidogrel.

Instructions for preparation

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

Add 5 ml sterile water for injections to one vial of bivalirudin and swirl gently until completely

dissolved and the solution is clear. 1 ml reconstituted solution contains 50 mg bivalirudin.

Withdraw 5 ml from the vial, and further dilute in a total volume of 50 ml of glucose 5% solution for

injection, 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 colourless solution, without any visible extraneous

matter.

Disposal

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

Incompatibilities

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 hydrochloride (HCl), diazepam,

prochlorperazine edisylate, reteplase, streptokinase and vancomycin HCl.

The following six medicinal products show dose-concentration incompatibilities with bivalirudin. See

section 6.2 from SmPC for the summary of compatible and incompatible concentrations of these

compounds. The medicinal products incompatible with bivalirudin at higher concentrations are:

dobutamine hydrochloride, famotidine, haloperidol lactate, labetalol hydrochloride, lorazepam and

promethazine HCl.

Contraindications

Bivalirudin is contraindicated in patients with:

a known hypersensitivity to the active substance or to any of the excipients listed in section 6.1of

SmPC, 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<30 ml/min) and in dialysis-dependent patients

(see section 4.3 of SmPC

).

Posology

Patients undergoing PCI, including patients with ST-segment elevation myocardial infarction

(STEMI) undergoing primary PCI

The recommended dose of bivalirudin 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 of 1.75 mg/kg body weight/hour

may be continued for up to 4 hours post-PCI and at a reduced dose of 0.25 mg/kg body weight/hour

for an additional 4-12 hours as clinical necessary. In STEMI patients the infusion of 1.75 mg/kg body

weight/hour should be continued for up to 4 hours post-PCI and continued at a reduced dose of 0.25

mg/kg body weight/hour for 4 – 12 hours as clinically necessary (see section 4.4).

Patients should be carefully monitored following primary PCI for signs and symptoms consistent with

myocardial ischaemia.

Patients with unstable angina/non-ST segment elevated myocardial infarction (UA/NSTEMI)

The recommended starting dose of bivalirudin for medically managed patients with acute coronary

syndrome (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 medically managed 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

infusion of bivalirudin should be continued until the time of surgery. Just prior to surgery, a 0.5 mg/kg

bolus dose should be administered followed by a 1.75 mg/kg/h intravenous infusion for the duration

of the surgery.

For patients who proceed to CABG surgery on pump, the intravenous 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 (UFH).

To ensure appropriate administration of bivalirudin, the completely dissolved, reconstituted and

diluted product should be thoroughly mixed prior to administration (see section 6.6 of SmPC). The

bolus dose should be administered by a rapid intravenous push to ensure that the entire bolus reaches

the patient before the start of the procedure.

Intravenous infusion lines should be primed with bivalirudin to ensure continuity of drug infusion

after delivery of the bolus.

The infusion dose should be initiated immediately after the bolus dose is administered, ensuring

delivery to the patient prior to the procedure, and continued uninterrupted for the duration of the

procedure. The safety and efficacy of a bolus dose of bivalirudin without the subsequent infusion has

not been evaluated and is not recommended even if a short PCI procedure is planned.

An increase in the activated clotting time (ACT) may be used as an indication that a patient has

received bivalirudin.

Renal impairment

Bivalirudin is contraindicated in patients with severe renal insufficiency (GFR<30 ml/min) and also in

dialysis-dependent patients (see section 4.3 of SmPC).

In patients with mild or moderate renal insufficiency, the ACS dose (0.1 mg/kg bolus/0.25 mg/kg/h

infusion) should not be adjusted.

Patients with moderate renal impairment (GFR 30-59 ml/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.

Hepatic impairment

No dose adjustment is needed.

(For full information on posology see section 4.2 of SmPC)

Shelf life

2 years

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

2-8°C. Store in a refrigerator (2°C-8°C). Do not freeze.

Diluted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C

and at 2°C-8°C. Do not store above 25°C. Do not freeze.

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°C unless reconstitution/dilution has taken place in

controlled and validated aseptic conditions.

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Bivalirudin Cipla 250 mg powder for concentrate for solution for injection/infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 250 mg bivalirudin

After reconstitution 1 ml contains 50 mg bivalirudin.

After dilution 1 ml contains 5 mg bivalirudin.

For the full list of excipients, see section 6.1

3.

PHARMACEUTICAL FORM

Powder for concentrate for solution for injection/infusion

White to off white lyophilized powder/cake.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Bivalirudin Cipla is indicated as an anticoagulant in adult patients undergoing percutaneous

coronary intervention (PCI), including patients with ST-segment elevation myocardial infarction

(STEMI) undergoing primary PCI.

Bivalirudin Cipla is also indicated for the treatment of adult patients with unstable angina/non-ST

segment elevation myocardial infarction (UA/NSTEMI) planned for urgent or early intervention.

Bivalirudin Cipla should be administered with acetylsalicylic acid and clopidogrel.

4.2

Posology and method of administration

Bivalirudin Cipla should be administered by a physician experienced in either acute coronary care

or in coronary intervention procedures.

Posology

Patients undergoing PCI, including patients with ST-segment elevation myocardial infarction

(STEMI) undergoing primary PCI

The recommended dose of bivalirudin 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 of 1.75 mg/kg body

weight/hour may be continued for up to 4 hours post-PCI and at a reduced dose of 0.25 mg/kg

body weight/hour for an additional 4-12 hours as clinical necessary. In STEMI patients the

infusion of 1.75 mg/kg body weight/hour should be continued for up to 4 hours post-PCI and

continued at a reduced dose of 0.25 mg/kg body weight/hour for an additional 4 – 12 hours as

clinically necessary (see section 4.4).

Patients should be carefully monitored following primary PCI for signs and symptoms consistent

with myocardial ischaemia.

Patients with unstable angina/non-ST segment elevated myocardial infarction (UA/NSTEMI)

The recommended starting dose of bivalirudin for medically managed patients with acute

coronary syndrome (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 medically managed 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 infusion of bivalirudin should be continued until the time of surgery. Just prior to

surgery, a 0.5 mg/kg bolus dose should be administered followed by a 1.75 mg/kg/h intravenous

infusion for the duration of the surgery.

For patients who proceed to CABG surgery on pump, the intravenous 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 (UFH).

To ensure appropriate administration of bivalirudin, the completely dissolved, reconstituted and

diluted product should be thoroughly mixed prior to administration (see section 6.6). The bolus

dose should be administered by a rapid intravenous push to ensure that the entire bolus reaches

the patient before the start of the procedure.

Intravenous infusion lines should be primed with bivalirudin to ensure continuity of drug infusion

after delivery of the bolus.

The infusion dose should be initiated immediately after the bolus dose is administered, ensuring

delivery to the patient prior to the procedure, and continued uninterrupted for the duration of the

procedure. The safety and efficacy of a bolus dose of bivalirudin without the subsequent infusion

has not been evaluated and is not recommended even if a short PCI procedure is planned.

An increase in the activated clotting time (ACT) may be used as an indication that a patient has

received bivalirudin.

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

1.75 mg/kg/h infusion dose is properly administered.

Where insufficient ACT increase is observed, the possibility of medication error should be

considered, for example inadequate mixing of bivalirudin or intravenous equipment failures.

The arterial sheath can be removed 2 hours after discontinuation of the bivalirudin infusion

without anticoagulation monitoring.

Use with other anticoagulant therapy

In STEMI patients undergoing primary PCI, standard pre-hospital adjunctive therapy should

include clopidogrel and may include the early administration of UFH (see section 5.1).

Patients can be started on bivalirudin 30 minutes after discontinuation of unfractionated heparin

given intravenously, or 8 hours after discontinuation of low molecular weight heparin given

subcutaneously.

Bivalirudin can be used in conjunction with a GP IIb/IIIa inhibitor. For further information

regarding the use of bivalirudin with or without a GP IIb/IIIa inhibitor, please see section 5.1.

Renal impairment

Bivalirudin is contraindicated in patients with severe renal insufficiency (GFR<30 ml/min) and

also in dialysis-dependent patients (see section 4.3).

In patients with mild or moderate renal insufficiency, the ACS dose (0.1 mg/kg bolus/0.25

mg/kg/h infusion) should not be adjusted.

Patients with moderate renal impairment (GFR 30-59 ml/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.

Patients with renal impairment should be carefully monitored for clinical signs of bleeding during

PCI, as clearance of bivalirudin is reduced in these patients (see section 5.2).

If the 5-minute 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.

Where insufficient ACT increase is observed, the possibility of medication error should be

considered, for example inadequate mixing of bivalirudin or intravenous equipment failures.

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

Increased awareness due to high bleeding risk should be exercised in the elderly because of age-

related decrease in renal function. Dose adjustments for this age group should be on the basis of

renal function.

Paediatric population

There is currently no indication for the use of bivalirudin in children less than 18 years old and no

recommendation on a posology can be made. Currently available data are described in sections

5.1 and 5.2.

Method of administration

Bivalirudin Cipla is intended for intravenous use.

Bivalirudin should be initially reconstituted to give a solution of 50 mg/ml bivalirudin.

Reconstituted material should then be further diluted in a total volume of 50 ml to give a solution

of 5 mg/ml bivalirudin.

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

For instructions on reconstitution and dilution of the medicinal product before administration, see

section 6.6.

4.3

Contraindications

Bivalirudin is contraindicated in patients with:

a known hypersensitivity to the active substance or to any of the excipients listed in section

6.1, 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<30 ml/min) and in dialysis-dependent patients

4.4

Special warnings and precautions for use

Bivalirudin 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 (T

is 25 ± 12

minutes).

Prolonged post PCI infusions of bivalirudin at recommended doses have not been associated with

an increased rate of bleeding (see section 4.2).

Co-administration with platelet inhibitors or anti-coagulants

Combined use of anti-coagulant medicinal products 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 haemostasis 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.

Acute stent thrombosis

Acute stent thrombosis (<24 hours) has been observed in patients with STEMI undergoing

primary PCI and has been managed by Target Vessel Revascularisation (TVR) (see sections 4.8

and 5.1). The majority of these cases were non-fatal. This increased risk of acute stent thrombosis

was observed during the first 4 hours following the end of the procedure among patients who

either discontinued the infusion of bivalirudin at the end of the procedure or received a continued

infusion at the reduced dose of 0.25 mg/kg/h (see section 4.2).

Patients should remain for at least 24 hours in a facility capable of managing ischaemic

complications and should be carefully monitored following primary PCI for signs and symptoms

consistent with myocardial ischaemia.

Brachytherapy

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

with bivalirudin.

Bivalirudin should be used with caution during beta brachytherapy procedures.

Excipient

Bivalirudin contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially “sodium-free”.

4.5

Interaction with other medicinal products and other forms of interaction

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, clinical

and biological parameters of haemostasis should be regularly monitored.

4.6

Fertility, pregnancy and lactation

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).

Bivalirudin should not be used during pregnancy unless the clinical condition of the woman

requires treatment with bivalirudin.

Breast-feeding

It is unknown whether bivalirudin is excreted in human milk. Bivalirudin should be administered

with caution in breast-feeding mothers.

4.7

Effects on ability to drive and use machines

Bivalirudin has no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

Summary of the safety profile

The most frequent serious and fatal adverse reactions are major haemorrhage (access site and

non access-site bleeding, including intracranial haemorrhage) and hypersensitivity, including

anaphylactic shock. Coronary artery thrombosis and coronary stent thrombosis with

myocardial infarction, and catheter thrombosis have each been reported rarely. Administration

errors may lead to fatal thrombosis.

In patients receiving warfarin, INR is increased by administration of bivalirudin.

Tabulated list of adverse reactions

Adverse reactions for bivalirudin from HORIZONS, ACUITY, REPLACE-2 trials and post-

marketing experience are listed by system organ class in Table 1.

Table 1. Adverse reactions for bivalirudin from HORIZONS, ACUITY, REPLACE-2 trials

and post-marketing experience

System organ

class

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)

Blood and

lymphatic system

disorders

Haemoglobin

decreased

Thrombocytopenia

Anaemia

Immune system

disorders

Hypersensitivity,

including

anaphylactic

reaction and shock,

including reports

with fatal outcome

Nervous system

disorders

Headache

Intracranial

haemorrhage

Eye disorders

Intraocular

haemorrhage

Ear and labyrinth

disorders

Ear haemorrhage

Cardiac disorders

Myocardial

infarction,

Cardiac

tamponade,

Pericardial

haemorrhage,

Coronary artery

thrombosis,

Angina pectoris.

Bradycardia,

Ventricular

tachycardia

Chest pain

Vascular disorders Minor

haemorrhage

at any site

Major

haemorrhage at

any site

including reports

with fatal

outcome

Haematoma,

Hypotension

Coronary stent

thrombosis

including reports

with fatal

outcome

Thrombosis

including reports

with fatal

outcome,

Arteriovenous

fistula,

Catheter

thrombosis,

Vascular

pseudoaneurysm

Compartment

syndrome

a, b

Respiratory,

thoracic and

mediastinal

disorders

Epistaxis,

Haemoptysis,

Pharyngeal

haemorrhage

Pulmonary

haemorrhage

Dyspnoea

Gastrointestinal

disorders

Gastrointestinal

haemorrhage

(including

haematemesis,

melaena,

oesophageal

haemorrhage, anal

haemorrhage),

Retroperitoneal

haemorrhage,

Gingival

haemorrhage,

Nausea

Peritoneal

haemorrhage,

Retroperitoneal

haematoma,

Vomiting

Skin and

subcutaneous

tissue disorders

Ecchymosis

Rash, Urticaria

Musculoskeletal

and connective

tissue disorders

Back pain,

Groin pain

Renal and urinary

disorders

Haematuria

General disorders

and administration

site conditions

Access site

haemorrhage,

Vessel puncture

site haematoma

>5 cm, Vessel

puncture site

haematoma <5

Injection site

reactions

(Injection site

discomfort,

Injection site pain,

Puncture site

reaction)

Investigations

INR increased

Injury, poisoning

Reperfusion

and procedural

complications

injury (no or slow

reflow),

Contusion

ADRs identified in post-marketing experience

Compartment syndrome has been reported as a complication of forearm haematoma following

administration of bivalirudin via the radial access route in post-marketing experience

Further detail regarding stent thrombosis is provided in section 4.8: The HORIZONS Trial

(Patients with STEMI undergoing primary PCI). For instructions for monitoring acute stent

thrombosis, see section 4.4.

Section 4.4 describes precautions for INR monitoring when bivalirudin is co-administered with

warfarin.

Description of selected adverse reactions

Haemorrhage

In all clinical studies bleeding data were collected separately from adverse reactions and are

summarised in Table 6 together with the bleeding definitions used for each study.

The HORIZONS Trial (Patients with STEMI undergoing primary PCI)

Platelets, bleeding and clotting

In the HORIZONS study both major and minor bleeding occurred commonly (≥1/100 and <1/10).

The incidence of major and minor bleeding was significantly less in patients treated with

bivalirudin versus patients treated with heparin plus a GP IIb/IIIa inhibitor. The incidence of

major bleeding is shown in Table 6. Major bleeding occurred most frequently at the sheath

puncture site. The most frequent event was a haematoma <5 cm at puncture site.

In the HORIZONS study, thrombocytopenia was reported in 26 (1. 6%) of bivalirudin-treated

patients and in 67 (3.9%) of patients treated with heparin plus a GP IIb/IIIa inhibitor. All of these

bivalirudin-treated patients received concomitant acetylsalicylic acid, all but 1 received

clopidogrel and 15 also received a GP IIb/IIIa inhibitor.

The ACUITY Trial (

Patients with unstable angina/non-ST segment elevated myocardial

infarction (UA/NSTEMI))

The following 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 GP IIb/IIIa

inhibitor and 4,603 were randomised to either unfractionated heparin or enoxaparin plus GP

IIb/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 for bivalirudin are listed by

system organ class in Table 1.

Platelets, bleeding and clotting

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

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 6 for the IIT population and Table 7 for the per protocol

population (patients receiving clopidogrel and acetylsalicylic acid). Both major and minor bleeds

were significantly less frequent with bivalirudin alone than the heparin plus GP IIb/IIIa inhibitor

and bivalirudin plus GP IIb/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 GP IIb/IIIa inhibitor. Mortality among

these patients was nil.

The REPLACE-2 Trial

(Patients undergoing PCI)

The following data is based on a clinical study of bivalirudin in 6,000 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 for bivalirudin are listed by system organ

class in Table 1.

Platelets, bleeding and clotting

In REPLACE-2, bleeding data were collected separately from adverse events. Major bleeding

rates for the intent-to-treat trial population 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 GP IIb/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.

In REPLACE-2 thrombocytopenia occurred in 20 bivalirudin-treated patients (0.7%). The

majority of these patients received concomitant acetylsalicylic acid and clopidogrel, and 10 out of

20 patients also received a GP IIb/IIIa inhibitor. Mortality among these patients was nil.

Acute cardiac events

The HORIZONS Trial

(Patients with STEMI undergoing primary PCI)

The following data are based on a clinical study of bivalirudin in patients with STEMI

undergoing primary PCI; 1,800 patients were randomised to bivalirudin alone, 1,802 were

randomised to heparin plus GP IIb/IIIa inhibitor. Serious adverse reactions were reported more

frequently in the heparin plus GP IIb/IIIa group than the bivalirudin treated group.

A total of 55.1% of patients receiving bivalirudin experienced at least one adverse event and

8.7% experienced an adverse drug reaction. Adverse drug reactions for bivalirudin are listed by

system organ class in Table 1.The incidence of stent thrombosis within the first 24 hours was

1.5% in patients receiving bivalirudin versus 0.3% in patients receiving UFH plus GP IIb/IIIa

inhibitor (p=0.0002). Two deaths occurred after acute stent thrombosis, 1 in each arm of the

study. The incidence of stent thrombosis between 24 hours and 30 days was 1. 2% in patients

receiving bivalirudin versus 1.9% in patients receiving UFH plus GP IIb/IIIa inhibitor

(p=0.1553). A total of 17 deaths occurred after subacute stent thrombosis, 3 in the bivalirudin arm

and 14 in the UFH plus GP IIb/IIIa arm. There was no statistically significant difference in the

rates of stent thrombosis between treatment arms at 30 days (p=0.3257) and 1 year (p=0.7754).

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 national reporting

system listed in Appendix V.

4.9

Overdose

Cases of overdose of up to 10 times the recommended dose have been reported in clinical trials.

Single bolus doses of bivalirudin up to 7.5 mg/kg have also been reported. Bleeding has been

observed in some reports of overdose.

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.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: antithrombotic agents, Direct thrombin inhibitors, ATC code:

B01AE06.

Mechanism of action

Bivalirudin Cipla 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, Arg

-Pro

, 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.

Pharmacodynamic effects

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 GP IIb/IIIa inhibitor.

Clinical efficacy and safety

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

procedures.

The HORIZONS Trial

(Patients with STEMI undergoing primary PCI)

The HORIZONS trial was a prospective, dual arm, single blind, randomised, multi-centre trial to

establish the safety and efficacy of bivalirudin in patients with STEMI undergoing a primary PCI

strategy with stent implantation with either a slow release paclitaxel-eluding stent (TAXUS

) or

an otherwise identical uncoated bare metal stent (Express2

). A total of 3,602 patients were

randomised to receive either bivalirudin (1,800 patients) or unfractionated heparin plus a GP

IIb/IIIa inhibitor (1,802 patients). All patients received acetylsalicylic acid and clopidogrel with

twice as many patients (approximately 64%) receiving a 600mg loading dose of clopidogrel than

a 300mg loading dose of clopidogrel.

Approximately 66% of patients were pre-treated with unfractionated heparin.

The dose of bivalirudin used in HORIZONS was the same as that used in the REPLACE-2 study

(0.75 mg/kg bolus followed by a 1.75 mg/kg body weight/hour infusion). A total of 92.9% of

patients treated underwent primary PCI as their primary management strategy.

The analysis and results for the HORIZONS trial at 30 days for the overall (ITT) population is

shown in Table 2. Results at 1 year were consistent with results at 30 days.

Bleeding definitions and outcomes from the HORIZONS trial are shown in Table 6.

Table 2

HORIZONS 30-day study results (intent-to-treat population)

Endpoint

Bivalirudin

(%)

Unfractionated

heparin + GP IIb/IIIa

inhibitor (%)

Relative Risk

[95% CI]

p-value*

N = 1,800

N = 1,802

30 day Composite

MACE

0.98

[0.75, 1.29]

0.8901

Major bleeding

0.58

[0.45, 0.74]

<0.0001

Ischaemic Components

All cause death

0.66

[0.44, 1.0]

0.0465

Reinfarction

1.06

[0.66, 1.72]

0.8003

Ischaemic target

vessel

revascularisation

1.29 [0.83,1.99]

0.2561

Stroke

1.17

[0.54, 2.52]

0.6917

*Superiority p-value.

Major Adverse Cardiac/Ischaemic Events (MACE) was defined as the

occurrence of any of the following; death, reinfarction, stroke or ischaemic target vessel

revascularisation.

Major bleeding was defined using the ACUITY bleeding scale.

ACUITY Trial

(Patients with unstable angina/non-ST segment elevated myocardial infarction

(UA/NSTEMI)

The ACUITY trial was a prospective, randomised open-label, trial of bivalirudin with or without

GP IIb/IIIa inhibitor (Arms B and C respectively) versus unfractionated heparin or enoxaparin

with GP IIb/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 intravenous bolus of 0.1 mg/kg followed by a continuous intravenous infusion of

0.25 mg/kg/h during angiography or as clinically warranted.

For patients undergoing PCI, an additional intravenous bolus of 0.5 mg/kg bivalirudin was

administered and the rate of intravenous 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 GP IIb/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 GP IIb/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

acetylsalicylic acid 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 acetylsalicylic acid 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)

Overall population (ITT)

Arm A

UFH/enox

+GP IIb/IIIa

inhibitor

(N=4,603)

%

Arm B

bival +GP

IIb/IIIa

inhibitor

(N=4,604)

%

B – A

Risk diff.

(95% CI)

Arm C

bival alone

(N=4,612)

%

C – A

Risk diff.

(95% CI)

30-day

Composite

ischaemia

0.48

(-0.60, 1.55)

0.55

(-0.53, 1.63)

Death

0.17

(-0.31, 0.66)

0.26

(-0.23, 0.75)

MI

0.04

(-0.84, 0.93)

0.45

(-0.46, 1.35)

Unplanned

revasc.

0.39

(-0.24, 1.03)

0.10

(-0.51, 0.72)

1-year

Composite

ischaemia

15.3

15.9

0.65

(-0.83, 2.13)

16.0

0.71

(-0.77, 2.19)

Death

0.04

(-0.83, 0.74)

-0.18

(-0.96, 0.60)

MI

0.19

(-0.84, 1.23)

0.83

(-0.22, 1.89)

Unplanned

revasc.

0.78

(-0.36, 1.92)

0.37

(-0.75, 1.50)

Table 4. ACUITY trial; 30-day and 1-year risk differences for the composite ischaemic

endpoint and its components for patients that received acetylsalicylic acid and clopidogrel

as per protocol*

Patients receiving acetylsalicylic acid & clopidogrel as per protocol*

Arm A

UFH/enox

+GP IIb/IIIa

inhibitor

(N=2,842)

%

Arm B

bival +GP

IIb/IIIa

inhibitor

(N=2,924)

%

B – A

Risk diff.

(95% CI)

Arm C

bival alone

(N=2,911)

%

C – A

Risk diff.

(95% CI)

30-day

Composite

ischaemia

0.03

(-1.32, 1.38)

-0.35

(-1.68, 0.99)

Death

-0.00

(-0.60, 0.60)

-0.14

(-0.72, 0.45)

MI

0.04

(-1.07, 1.14)

-0.08

(-1.18, 1.02)

Unplanned

revasc.

0.23

(-0.61, 1.08)

-0.41

(-1.20, 0.39)

1-year

Composite

ischaemia

16.1

16.8

0.68

(-1.24, 2.59)

15.8

-0.35

(-2.24, 1.54)

Death

0.20

(-0.78, 1.19)

-0.36

(-1.31, 0.59)

MI

0.60

(-0.71, 1.91)

0.19

(-1.11, 1.48)

Unplanned

revasc.

10.0

0.59

(-0.94, 2.12)

-0.53

(-2.02, 0.96)

*clopidogrel pre-angiography or pre-PCI

The incidence of both ACUITY-scale and TIMI-scale bleeding events up to day 30 for the intent-

to-treat population is presented in Table 6. The incidence of both ACUITY-scale and TIMI-scale

bleeding events to day 30 for the per protocol population are presented in Table 7. The advantage

of bivalirudin over UFH/enoxaparin plus GP IIb/IIIa inhibitor in terms of bleeding events was

only observed in the bivalirudin monotherapy arm.

The REPLACE-2 Trial

(Patients undergoing PCI)

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 5. Bleeding definitions

and outcomes from the REPLACE-2 trial are shown in Table 6.

Table 5. REPLACE-2 study results: 30-day endpoints (intent-to-treat and per-protocol

populations

Intent-to-treat

Per-protocol

Endpoint

bivalirudin

(N=2,994)

%

heparin

+ GP IIb/IIIa

inhibitor

(N=3,008)

%

bivalirudin

(N=2,902)

%

heparin

+ GP IIb/IIIa

inhibitor

(N=2,882)

%

Quadruple endpoint

10.0

10.0

Triple endpoint*

Components:

Death

Myocardial Infarction

Major bleeding** (based on

non-TIMI criteria - see section

4.8)

Urgent revascularisation

* excludes major bleeding component. **p<0.001

Table 6. Major bleeding rates in clinical trials of bivalirudin 30 day endpoints for intent-to-

treat populations

Bivalirudin (%)

Bival + GP

IIb/IIIa

inhibitor

(%)

UFH/Enox

1

+ GP IIb/IIIa inhibitor

(%)

REPLACE-

ACUITY

HORIZONS ACUITY

REPLACE-

ACUITY

HORIZONS

N = 2,994

N = 4,612

N = 1,800

N = 4,604

N = 3,008

N = 4,603 N = 1,802

Protocol

defined

major

bleeding

TIMI

Major

(non-

CABG)

Bleeding

Enoxaparin was used as comparator in ACUITY only.

Table 7. ACUITY trial; bleeding events up to day 30 for the population of patients who

received acetylsalicylic acid and clopidogrel as per protocol*

UFH/enox + GP

IIb/IIIa inhibitor (N=

2,842) %

Bival + GP IIb/IIIa

inhibitor (N=2,924)

%

Bival alone (N=2,911) %

ACUITY scale major

bleeding

TIMI scale major

bleeding

*clopidogrel pre-angiography or pre-PCI

Bleeding Definitions

REPLACE-2

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.

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, use of any

blood product transfusion.

Major bleeding in the HORIZONS study

was also defined using the

ACUITY scale.

TIMI major bleeding

was defined as intracranial bleeding or a decrease in

haemoglobin concentration ≥5 g/dl.

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

bivalirudin in patients with HIT/HITTS.

Paediatric population

In clinical study TMC-BIV-07-01, the pharmacodynamic response as measured by ACT was

consistent with adult studies. The ACT increased in all patients – from neonates to older children

as well as adults-with increasing bivalirudin concentrations. The ACT vs concentration data

suggest a trend for a lower concentration response curve for adults as compared to older children

(6 years to < 16 years) and younger children (2 years to <6 years), and for older children

compared to infants (31 days to <24 months) and neonates (birth to 30 days). Pharmacodynamic

models indicated that this effect is due to a higher baseline ACT in neonates and infants than in

older children. However, the maximal ACT values for all groups (adults and all paediatric

groups) converge at a similar level near an ACT of 400 seconds. The clinical utility of ACT in

neonates and children should be considered with caution considering their developmental

haematological state.

Thrombotic (9/110, 8.2%) and major bleeding events (2/110, 1.8%) were observed in the study.

Other frequently reported adverse events were decreased pedal pulse, catheter site haemorrhage,

abnormal pulse, and nausea (8.2%, 7.3%, 6.4% and 5.5%, respectively).

Five patients had a post-

baseline nadir platelet count of <150,000 cells/mm

, representing a ≥50% decrease in platelets

from baseline. All 5 events were associated with additional cardiac procedures employing heparin

anticoagulation (n=3) or with infections (n=2). A population pharmacokinetic/pharmacodynamic

analysis, and an Exposure and Adverse Event Assessment Model based on the data from this

study determined that in paediatric patients, use of the adult dosing with plasma levels similar to

that achieved in adults was associated with lower levels of thrombotic events with no impact on

bleeding events (see section 4.2).

5.2

Pharmacokinetic properties

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 Arg

-Pro

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 impairment

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 impairment

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 8).

Table 8. Pharmacokinetic parameters for bivalirudin in patients with normal and impaired

renal function

Renal function (GFR)

Clearance (ml/min/kg)

Half-life (minutes)

Normal renal function (≥ 90ml/min)

Mild renal impairment (60-89 ml/min)

Moderate renal impairment (30-59 ml/min)

Severe renal impairment (10-29 ml/min)

Dialysis dependent patients (off-dialysis)

3.5 hours

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.

Paediatric population

In a clinical trial of 110 paediatric patients (neonates to <16 years of age) undergoing

percutaneous intravascular procedures, the safety, pharmacokinetic and pharmacodynamic profile

of bivalirudin was evaluated [TMC-BIV-07-01]. The approved adult weight-based intravenous

bolus dose of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hour was studied and

pharmacokinetic/pharmacodynamic analysis found a response similar to that of adults, although

weight-normalized clearance (ml/min/kg) of bivalirudin was higher in neonates than in older

children and decreased with increasing age.

5.3

Preclinical safety data

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.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipient

Mannitol

Sodium hydroxide

6.2

Incompatibilities

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 hydrochloride (HCl), diazepam,

prochlorperazine edisylate, reteplase, streptokinase and vancomycin HCl.

The following six medicinal products show dose-concentration incompatibilities with bivalirudin.

Table 9 summarises compatible and incompatible concentrations of these compounds. The

medicinal products incompatible with bivalirudin at higher concentrations are: dobutamine

hydrochloride, famotidine, haloperidol lactate, labetalol hydrochloride, lorazepam and

promethazine HCl.

Table 9. Medicinal products with dose concentration incompatibilities to bivalirudin.

Medicinal products with dose

concentration incompatibilities

Compatible

concentrations

Incompatible

concentrations

Dobutamine HCl

4 mg/ml

12.5 mg/ml

Famotidine

2 mg/ml

10 mg/ml

Haloperidol lactate

0.2 mg/ml

5 mg/ml

Labetalol HCl

2 mg/ml

5 mg/ml

Lorazepam

0.5 mg/ml

2 mg/ml

Promethazine HCl

2 mg/ml

25 mg/ml

6.3

Shelf life

2 years

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 24 hours

at 2-8°C. Store in a refrigerator (2°C-8°C). Do not freeze.

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

25°C and at 2°C-8°C. Do not store above 25°C. Do not freeze.

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°C unless reconstitution/dilution has taken

place in controlled and validated aseptic conditions.

6.4

Special precautions for storage

This medicinal product does not require any specific storage condition.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

6.5

Nature and contents of container

10 ml vials (Type 1 glass) with stopper (butyl rubber) with seal (aluminum), containing 250 mg

bivalirudin.

Pack sizes: 1 and 10 vials.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

Instructions for preparation

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

Add 5 ml sterile water for injections to one vial of bivalirudin and swirl gently until completely

dissolved and the solution is clear. 1 ml reconstituted solution contains 50 mg bivalirudin.

Withdraw 5 ml from the vial, and further dilute in a total volume of 50 ml of glucose 5% solution

for injection, 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 colourless solution, without any visible

extraneous matter.

Disposal

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

requirements.

7.

MARKETING AUTHORISATION HOLDER

<To be completed nationally>

8.

MARKETING AUTHORISATION NUMBER(S)

To be completed nationally

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<To be completed nationally>

10.

DATE OF REVISION OF THE TEXT

2020-03-26

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