Bivalirudin Accord

Package leaflet: Information for the user

Bivalirudina Accord 250 mg powder for concentrate for solution for injection/infusion

Generic medicine
Please read all of this leaflet carefully before you use this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

1. What Bivalirudina Accord is and what it is used for
2. What you need to know before you use Bivalirudina Accord
3. How to use Bivalirudina Accord
4. Possible side effects
5. How to store Bivalirudina Accord
6. Contents of the pack and other information

1. What Bivalirudina Accord is and what it is used for

Bivalirudina Accord contains a substance called bivalirudin, which is an antithrombotic medicine.
Antithrombotics are medicines that prevent the formation of blood clots (thrombosis).
Bivalirudina Accord is used to treat patients:

• with chest pain due to heart disease (acute coronary syndrome - ACS)
• undergoing a surgical procedure aimed at treating blockages in blood vessels (angioplasty and/or percutaneous coronary intervention - PCI).

2. What you need to know before using Bivalirudin Accord

Do not use Bivalirudin Accord

• if you are allergic to bivalirudin or to any of the other ingredients of this medicine (listed in section 6) or to hirudins (other medicines that thin the blood).
• if you currently have, or have recently had gastrointestinal, intestinal, bladder or other organ bleeding, for example if you have noticed traces of blood in your stools or urine (except during menstruation).
• if you currently have, or have previously had, coagulation disorders (low platelet count in the blood).
• if you have severe hypertension (high blood pressure).
• if you have an infection of the heart tissue.
• if you have severe kidney problems or require dialysis.

If in doubt, consult your doctor.
Warnings and precautions
Talk to your doctor before using Bivalirudin Accord

• if bleeding occurs (if this happens, treatment with Bivalirudin Accord will be stopped). During treatment, your doctor will monitor you for any signs of bleeding
• if you have previously been treated with medicines similar to Bivalirudin Accord (e.g. lepirudin)
• before starting the injection or infusion, your doctor will explain to you the signs of an allergic reaction. Such a reaction is not common (it may occur in 1 out of 100 people)
• if you are currently receiving radiation therapy to the blood vessels supplying the heart (a treatment called beta or gamma brachytherapy).

After being treated with Bivalirudin Accord for a heart condition, you must remain in hospital for at least 24 hours and be monitored for any symptoms or signs resembling those related to the heart condition for which you were admitted.
Children and adolescents

• If you are of pediatric age (under 18 years of age), this medicine is not suitable for you.

Other medicines and Bivalirudin Accord
Inform your doctor or pharmacist

• if you are taking, have recently taken, or might take any other medicines
• if you are taking blood thinners or medicines that prevent blood clots (anticoagulants or antiplatelets, e.g. warfarin, dabigatran, apixaban, rivaroxaban, acetylsalicylic acid, clopidogrel, prasugrel, ticagrelor).

These medicines may increase the risk of adverse effects such as bleeding when administered together with Bivalirudin Accord. Bivalirudin Accord may alter blood test results used to monitor warfarin (INR test).
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
Bivalirudin Accord must not be used during pregnancy unless clearly necessary. Your doctor will decide whether this treatment is suitable for you. If you are breastfeeding, your doctor will decide whether Bivalirudin Accord should be used.
Driving and using machines
The effects of this medicine are known to be of short duration. Bivalirudin Accord is administered only when a patient is in hospital. Therefore, it is unlikely to affect your ability to drive or operate machinery.
Bivalirudin Accord contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e. it is essentially “sodium-free”.

3. How to use Bivalirudina Accord

Your treatment with Bivalirudina Accord will be supervised by a doctor. The doctor will decide the
amount of Bivalirudina Accord to administer and will prepare the medicine.
The dose administered depends on your body weight and the type of therapy you are receiving.
Dosage
For patients with acute coronary syndrome (ACS) receiving medical treatment, the recommended initial dose is:

• 0.1 mg/kg body weight as an intravenous injection, followed by intravenous infusion (intravenous drip) of 0.25 mg/kg body weight per hour for up to 72 hours.

If, after this dose, you undergo a percutaneous coronary intervention (PCI), the dosage will be increased to:

• 0.5 mg/kg body weight as an intravenous injection, followed by intravenous infusion of 1.75 mg/kg body weight per hour for the duration of the PCI.
• When this treatment is completed, the infusion rate may return to 0.25 mg/kg body weight per hour for an additional 4–12 hours.

If you are scheduled to undergo coronary artery bypass surgery, bivalirudin therapy will be
discontinued one hour before surgery, or you will be given an additional dose of 0.5 mg/kg body
weight via injection, followed by an infusion of 1.75 mg/kg body weight per hour for the duration of the surgery.
For patients undergoing a percutaneous coronary intervention (PCI) as initial treatment, the recommended dose is:

• 0.75 mg/kg body weight as an intravenous injection, immediately followed by an intravenous infusion (intravenous drip) of 1.75 mg/kg body weight per hour for at least the duration of the percutaneous coronary intervention. The intravenous infusion may continue at this dose for up to 4 hours after PCI, and for patients with STEMI (i.e., patients with a severe type of heart attack), it should continue at this dose for up to 4 hours. The infusion may then be followed by an infusion at the reduced dose of 0.25 mg/kg body weight for an additional 4–12 hours.

The dose of Bivalirudina Accord may be reduced if you have kidney problems.
In elderly patients with reduced kidney function, a dose reduction may be necessary.
Your doctor will decide the duration of your treatment.
Bivalirudina Accord is administered by injection, followed by infusion (intravenous drip), into a vein (never into a muscle). Administration and monitoring of effects must be supervised by a doctor experienced in the treatment of patients with heart disease.
If you use more medicine than you should
The doctor will decide how to manage your treatment, including discontinuation of the drug and monitoring for adverse effects.
If you have any doubts about how to use this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them. If you experience any of the following potentially serious side effects:
o if you are in hospital: tell your doctor or nurse immediately
o after leaving hospital: contact your doctor directly or go immediately to the Emergency Department of the nearest hospital

The most common serious side effect (may occur in up to 1 in 10 people) associated with bivalirudin treatment is major bleeding, which could occur in any part of the body (e.g. stomach, gastrointestinal tract (including vomiting blood or blood in stools), abdomen, lungs, groin, bladder, heart, eye, ear, nose, or brain). This may rarely lead to stroke or death. Swelling or pain in the groin or arm, back pain, bruising, headache, coughing up blood, pink or red urine, sweating, fainting, nausea, or dizziness due to low blood pressure may be signs of internal bleeding. Bleeding is more likely when bivalirudin is used together with other anticoagulant or antithrombotic medicines (see section 2 “Other medicines and Bivalirudina Accord”).

• Bleeding and bruising at the injection site (after PCI treatment) may be painful. In rare cases, surgical intervention may be required to repair a blood vessel in the groin (fistula, pseudoaneurysm) (may occur in up to 1 in 1,000 people). In uncommon cases (may occur in up to 1 in 100 people), platelet count may be low, which could worsen any bleeding. Gum bleeding (uncommon, may occur in up to 1 in 100 people) is usually not serious.
• Allergic reactions are uncommon side effects (may occur in up to 1 in 100 people) and are usually not serious, but they may become serious under certain circumstances and, in rare cases, may be fatal due to low blood pressure (shock). They may start with mild symptoms such as itching, skin redness, rash, or small skin bumps. Occasionally, reactions may be more severe, with itching in the throat, throat tightness, swelling of the eyes, face, tongue, or lips, high-pitched whistling sound during inhalation (stridor), difficulty breathing or wheezing.
• Thrombosis (blood clot) is an uncommon side effect (may occur in up to 1 in 100 people), which may lead to serious or life-threatening complications such as heart attacks. Thrombosis includes coronary artery thrombosis (blood clot in the heart arteries or in a stent, experienced as a heart attack and potentially fatal) and/or catheter thrombosis, both of which are rare (may occur in up to 1 in 1,000 people).

If you experience any of the following side effects (potentially less severe):
o if you are in hospital: inform your doctor or nurse
o after leaving hospital: try to contact your doctor first. If you cannot reach your doctor, go immediately to the Emergency Department of the 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 (low blood cell count)
• Haematoma (bruising)

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

• Nausea (feeling unwell) and/or vomiting

Rare side effects (may affect up to 1 in 1,000 people):

• Increase in INR test values (blood test results used to monitor warfarin therapy) (see section 2, “Other medicines and Bivalirudina Accord”)
• Angina or chest pain
• Slow heart rate
• Fast heart rate
• Shortness of breath
• Reperfusion injury (no-reflow or slow-reflow): reduced blood flow in the coronary arteries following reopening.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at the website
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Bivalirudin Accord

Since Bivalirudin Accord is a medicinal product intended exclusively for hospital use, storage of Bivalirudin Accord falls under 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 stated on the label and carton after “EXP”. The expiry date refers to the last day of that month.
Reconstituted solution: store in a refrigerator at 2-8°C. Do not freeze.
Diluted solution: do not store at temperatures above 25°C. Do not refrigerate. Do not freeze.
The solution should be clear to slightly opalescent and colourless to yellowish. The doctor will check the solution and discard it if it contains particles or is discoloured.

6. Package contents and other information

What Bivalirudina Accord contains

• The active substance is bivalirudin.
• Each vial contains 250 mg of bivalirudin.
• After reconstitution (adding 5 ml of water for injections to the vial to dissolve the powder), 1 ml contains 50 mg of bivalirudin.
• After dilution (mixing 5 ml of the reconstituted solution into an infusion bag [total volume 50 ml] containing glucose solution or sodium chloride solution), 1 ml contains 5 mg of bivalirudin.
  The other ingredients are mannitol (E421) and sodium hydroxide (for pH adjustment).

Description of the appearance of Bivalirudina Accord and contents of the pack
Bivalirudina Accord is a powder for concentrate for solution for injection/infusion (powder for concentrate).
Bivalirudina Accord is a sterile powder, white to off-white in colour, contained in a glass vial.
Bivalirudina Accord is available in cartons containing 1 vial, 5 vials or 10 vials.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Accord Healthcare S.L.U.
World Trade Center,
Moll de Barcelona,
s/n, Edifici Est 6ª planta,
08039 Barcelona,
Spain

Manufacturer
Laboratory Reig Jofré S.A.
C/Gran Capitán, 10, Sant Joan Despí,
08970 Barcelona,
Spain

This medicinal product is authorized in the Member States of the European Economic Area and the United Kingdom (Northern Ireland) under the following names:

The following information is intended for healthcare professionals only:

Healthcare professionals should consult the Summary of Product Characteristics for complete prescribing information.
Bivalirudina Accord is indicated as an anticoagulant in adult patients undergoing percutaneous coronary intervention (PCI), including patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).
Bivalirudina Accord is also indicated for the treatment of adult patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) when undergoing urgent or immediate intervention.
Bivalirudina Accord must be administered with acetylsalicylic acid and clopidogrel.

Instructions for Preparation
Aseptic techniques must be used for the preparation and administration of Bivalirudina Accord.
Add 5 ml of sterile water for injections to a vial of Bivalirudina Accord and gently rotate until dissolution is complete and the solution is clear. Complete reconstitution may take up to 3–4 minutes.
Withdraw 5 ml from the vial and further dilute in a total volume of 50 ml of 5% glucose injection solution or 0.9% sodium chloride injection solution (9 mg/ml) to obtain a final bivalirudin concentration of 5 mg/ml.
The reconstituted/diluted solution should be inspected visually for particulate matter and discoloration. Solutions containing particulates or showing discoloration must not be used.
The reconstituted/diluted solution will range from clear to slightly opalescent and from colourless to pale yellow.

Reconstituted concentrate for solution for injection or infusion
The reconstituted solution (concentration 50 mg/ml) has a pH between 4.6 and 6.0 and an osmolality in the range of 250–450 mOsmol/kg.
Unused medicinal product and waste material must be disposed of in accordance with local regulations.

Incompatibilities
The following medicinal products must not be administered through the same intravenous line as bivalirudin due to cloudiness, formation of microparticles, 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 concentration-dependent incompatibility with bivalirudin. See section 6.2 for a summary of compatible and incompatible concentrations of these compounds. Medicinal products incompatible with bivalirudin at higher concentrations are: dobutamine hydrochloride, famotidine, haloperidol lactate, labetalol hydrochloride, lorazepam, and promethazine HCl.

Contraindications
Bivalirudina Accord is contraindicated in patients with:

• confirmed 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 due to haemostatic disorders and/or irreversible coagulation disorders
• uncontrolled severe hypertension
• subacute bacterial endocarditis
• severe renal impairment (GFR < 30 ml/min) and in patients dependent on dialysis (see section 4.3 of the SmPC).

Dosage
Patients undergoing percutaneous coronary intervention (PCI), including patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI
The recommended dose of bivalirudin for patients undergoing PCI consists of an intravenous bolus of 0.75 mg/kg body weight, immediately followed by a continuous intravenous infusion of 1.75 mg/kg body weight/hour for the duration of the procedure. The infusion of 1.75 mg/kg body weight/hour may be continued for up to 4 hours after PCI, followed by a reduced dose of 0.25 mg/kg body weight/hour for an additional 4–12 hours, if clinically necessary.
In patients with STEMI, the infusion of 1.75 mg/kg body weight/hour should be continued for up to 4 hours after PCI and then continued at a reduced dose of 0.25 mg/kg body weight/hour for an additional 4–12 hours, if clinically necessary (see section 4.4).
Patients should be closely monitored after primary PCI for signs and symptoms consistent with myocardial ischaemia.

Patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI)
The recommended initial dose of bivalirudin in patients receiving only pharmacological treatment for acute coronary syndromes (ACS) consists of an intravenous bolus of 0.1 mg/kg followed by an infusion of 0.25 mg/kg/hour. Patients receiving only pharmacological treatment may continue the infusion of 0.25 mg/kg/hour for up to 72 hours.
If patients receiving only pharmacological treatment undergo PCI, an additional bolus of 0.5 mg/kg of bivalirudin should be administered before the procedure, and the infusion rate should be increased to 1.75 mg/kg/hour during the intervention.
After PCI, the reduced infusion dose of 0.25 mg/kg/hour may be resumed for 4–12 hours if clinically necessary.
For patients undergoing off-pump coronary artery bypass grafting (CABG), the intravenous infusion of bivalirudin should be continued throughout the procedure. Immediately before surgery, a bolus of 0.5 mg/kg should be administered, followed by an intravenous infusion of 1.75 mg/kg/hour for the duration of the procedure.
For patients undergoing on-pump coronary artery bypass grafting (CABG), the intravenous infusion of bivalirudin should be continued until one hour before surgery, after which the infusion should be discontinued and the patient treated with unfractionated heparin (UFH).

To ensure appropriate administration of bivalirudin, the fully dissolved, reconstituted, and diluted product must be thoroughly mixed before administration (see section 6.6). The bolus dose should be administered as a rapid intravenous injection 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 bolus administration.
The infusion should be started immediately after administration of the bolus dose to ensure that the patient receives treatment before the procedure and should be continued uninterrupted for the duration of the procedure. The safety and efficacy of a bivalirudin bolus dose without subsequent infusion have not been evaluated, and this is not recommended, even for brief PCI procedures.
An increase in activated clotting time (ACT) may be used to confirm that a patient has received bivalirudin.

Renal impairment
Bivalirudina Accord is contraindicated in patients with severe renal impairment (glomerular filtration rate (GFR) < 30 ml/min) and in patients dependent on dialysis (see section 4.3).
The dose for ACS (0.1 mg/kg bolus and 0.25 mg/kg/hour infusion) does not need to be adjusted in patients with mild or moderate renal impairment.
Patients with moderate renal impairment (GFR 30–59 ml/min) undergoing PCI (treated with bivalirudin for ACS or not) should receive the infusion at a reduced rate of 1.4 mg/kg/hour. The bolus dose should not be adjusted from the dosage previously described under ACS or PCI above.

Hepatic impairment
No dose adjustment is required.
(For complete dosage information, see section 4.2 of the SmPC)

Shelf Life
3 years
Reconstituted solution: chemical and physical in-use stability has been demonstrated for 24 hours at 2–8°C.
Store at 2°C–8°C in a refrigerator. Do not freeze. From a microbiological standpoint, unless the method of opening/reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, the in-use storage time and conditions prior to use are the responsibility of the user.
Diluted solution: chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.
Do not store above 25°C. Do not refrigerate. Do not freeze. From a microbiological standpoint, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, the in-use storage time and conditions prior to use are the responsibility of the user.