Bivalirudin accord

Package leaflet: Information for the patient

Biwalirudyna Accord, 250 mg, powder for solution for injection/infusion
Bivalirudinum
Please read all of this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you personally. Do not pass it on to others. It may harm them even if their symptoms are the same as yours.
• If you experience any side effects, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Leaflet contents:

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

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

Biwalirudyna Accord contains a substance called bivalirudin, which is an anticoagulant medicine. Anticoagulant medicines prevent the formation of blood clots (thrombosis).
Biwalirudyna Accord is used to treat patients:

• with chest pain caused by heart disease (Acute Coronary Syndrome - ACS),
• who are undergoing interventional treatment of blocked blood vessels (angioplasty and/or percutaneous coronary intervention - PCI).

2. Information before using Biwalirudyna Accord

When not to use Biwalirudyna Accord

• if the patient is allergic to bivalirudan or any of the other ingredients of this medicine (listed in section 6) or to hirudin derivatives (other anticoagulant medicines),
• if the patient currently has or recently had bleeding from the stomach, intestines, urinary bladder or other internal organs, for example if blood has been noticed in the stool or urine (this does not include menstruation),
• if the patient currently has or has had blood clotting disorders (low platelet count),
• if the patient has high blood pressure,
• if the patient has an infection of the heart tissue,
• in cases of severe kidney disease or in dialysed patients.

If in doubt, consult a doctor.
Warnings and precautions
Before starting treatment with Biwalirudyna Accord, discuss this with your doctor.

• if bleeding occurs (in such a case, treatment with Biwalirudyna Accord will be stopped); during the entire treatment period, the doctor will monitor the patient for any signs of bleeding;
• if the patient has previously been treated with medicines similar to Biwalirudyna Accord (e.g. lepirudin);
• before starting the injection or intravenous infusion, the doctor will inform the patient about the symptoms of an allergic reaction; such reactions occur not frequently (may occur in no more than 1 in 100 people);
• if the patient is undergoing radiation therapy within the blood vessels supplying the heart (treatment known as beta or gamma brachytherapy).

After receiving Biwalirudyna Accord due to a coronary incident, the patient should remain in hospital for at least 24 hours and should be monitored for any symptoms or signs suggestive of a recurrent coronary event that led to hospitalization.
Children and adolescents

• use of this medicine in children (under 18 years of age) is not recommended

Biwalirudyna Accord and other medicines
Inform your doctor or pharmacist about:

• all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take,
• all anticoagulant or antiplatelet medicines being taken to prevent blood clots (anticoagulants or antiplatelet agents, e.g. warfarin, dabigatran, apixaban, rivaroxaban, acetylsalicylic acid, clopidogrel, prasugrel, ticagrelor).

These medicines, when used together with Biwalirudyna Accord, may increase the risk of bleeding.
Biwalirudyna Accord may affect the international normalized ratio (INR) value.
Pregnancy and breastfeeding
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to become pregnant, she should consult her doctor before using this medicine.
Biwalirudyna Accord should not be used during pregnancy unless absolutely necessary. The treating physician will decide whether its use is necessary. During breastfeeding, the doctor will decide whether Biwalirudyna Accord should be used.
Driving and operating machinery
The effects of this medicine are known and short-lived. Biwalirudyna Accord is administered only when the patient is in hospital. Therefore, it is unlikely that the medicine will affect the ability to drive or operate machinery.
Biwalirudyna Accord contains sodium
This medicine contains less than 1 mmol of sodium (23 mg) per vial, which means it is essentially "sodium-free".
3. How to use Biwalirudyna Accord
Treatment with Biwalirudyna Accord is carried out under medical supervision. The doctor decides on the dosage and prepares the medicine.
The dose depends on body weight and the type of treatment.
Dosage
For patients with acute coronary syndromes (ACS) treated pharmacologically,
the recommended initial dose is:

• 0.1 mg/kg body weight as an intravenous bolus injection, followed by continuous intravenous infusion at 0.25 mg/kg body weight per hour for up to 72 hours.

If subsequently a percutaneous coronary intervention (PCI) becomes necessary, the dosage should be increased to:

• 0.5 mg/kg body weight as an intravenous bolus injection, followed by continuous intravenous infusion at 1.75 mg/kg body weight per hour for the entire duration of PCI.
• when treatment is completed, the infusion may be continued at the dose of 0.25 mg/kg body weight per hour for an additional 4 to 12 hours.

If coronary artery bypass graft (CABG) surgery becomes necessary, bivalirudin treatment should be discontinued one hour before the procedure, or an additional bolus dose of 0.5 mg/kg body weight should be administered, followed by intravenous infusion at 1.75 mg/kg body weight per hour throughout the duration of surgery.
For patients initiating treatment with percutaneous coronary intervention (PCI), the recommended
dosage is as follows:

• 0.75 mg/kg body weight as an intravenous bolus injection, followed immediately by continuous intravenous infusion at 1.75 mg/kg body weight per hour for at least the entire duration of PCI. The intravenous infusion may be continued at this dose for up to 4 hours after completion of PCI, and in patients with ST-segment elevation myocardial infarction (STEMI) (patients with a severe type of heart attack), the infusion should be continued at this dose for 4 hours. After this, the infusion may be continued at a reduced dose of 0.25 mg/kg body weight per hour for an additional 4 to 12 hours.

If the patient has kidney problems, the dose of Biwalirudyna Accord may be reduced.
In elderly patients, dose reduction may be necessary if renal function is impaired.
The doctor must decide on the duration of treatment.
Biwalirudyna Accord is administered as intravenous bolus injections, followed by continuous infusion (intravenous drip) into a vein (never intramuscularly). The medicine is administered under the supervision of a physician experienced in treating patients with heart disease.
Overdose
The doctor will decide on the appropriate management, including discontinuation of the medicine and monitoring the patient for signs of adverse effects.
If there are any further doubts regarding the use of this medicine, consult a doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
If any of the following potentially life-threatening adverse reactions occur:

• during hospital stay: report them immediately to your doctor or nurse;
• after leaving hospital: contact your doctor immediately or go straight to the nearest hospital emergency department

The most common (may occur in up to 1 in 10 people) serious adverse reaction associated with bivalirudin treatment is major bleeding, which may occur in any part of the body (e.g. stomach, gastrointestinal tract (including vomiting blood or blood in stool), abdomen, lungs, groin, bladder, heart, eye, ear, nose or brain). In rare cases, this may lead to stroke or death. Swelling or pain in the groin or arm, back pain, bruising, headache, bloody sputum, pink or red-coloured urine, sweating, feeling weak or faint, or dizziness due to low blood pressure may be signs of internal bleeding. The risk of bleeding is higher when bivalirudin is used in combination with other anticoagulant or antiplatelet medicines (see section 2 “Biwalirudyna Accord and other medicines”).

• Bleeding and bruising at the injection site (after PCI treatment), which may be accompanied by pain. In rare cases, this may require surgical intervention to repair a blood vessel in the groin (fistula, pseudoaneurysm) (may occur in up to 1 in 1,000 people). Thrombocytopenia (reduced platelet count) is uncommon (may occur in up to 1 in 100 people) and may lead to increased bleeding. Bleeding gums (uncommon, may occur in up to 1 in 100 people) is usually not serious.
• Allergic reactions are uncommon (may occur in up to 1 in 100 people) and usually not serious, but may become serious under certain circumstances and, in rare cases, may be fatal due to a drop in blood pressure (shock). They may begin with localized symptoms such as itching, skin redness, rash or small skin nodules. Sometimes, reactions may be more severe, with throat itching, sensation of tightness in the throat, swelling of the eyes, face, tongue or lips, high-pitched wheezing during inhalation (wheezing), difficulty breathing or noisy breathing during exhalation (stridor).
• Thrombosis (blood clot formation) is an uncommon adverse reaction (may occur in up to 1 in 100 people) and may lead to serious, even fatal complications such as heart attack. Thrombosis includes coronary artery thrombosis (a clot in the heart arteries or stent, experienced as a heart attack, which may also be fatal) and (or) catheter-related thrombosis, both of which are rare (may occur in up to 1 in 1,000 people).

If any of the following (potentially less serious) adverse reactions occur:

• during hospital stay: report them immediately to your doctor or nurse;
• after leaving hospital: consult your doctor first. If this is not possible, go immediately to the nearest hospital emergency department

Very common adverse reactions (may occur in more than 1 in 10 people):

• Minor bleeding

Common adverse reactions (may occur in up to 1 in 10 people):

• Anaemia (low number of red blood cells)
• Haematoma (bruising)

Uncommon adverse reactions (may occur in up to 1 in 100 people):

• Nausea and (or) vomiting

Rare adverse reactions (may occur in up to 1 in 1,000 people):

• Increased INR (International Normalised Ratio) (see section 2, Biwalirudyna Accord and other medicines)
• Angina or chest pain
• Slow heart rate
• Fast heart rate
• Shortness of breath
• Reperfusion injury (incomplete or no restoration of flow): impaired blood flow in the coronary arteries after restoration of circulation

Reporting of adverse reactions
If any adverse symptoms occur, including any adverse reactions not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Reactions of Medicinal Products at the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps provide more information on the safety of the medicine.

5. How to store Biwalirudyna Accord

Since Biwalirudyna Accord is a medicine intended exclusively for hospital use,
storage of Biwalirudyna Accord is the responsibility of medical personnel.
Keep the 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 the stated month.
Reconstituted solution: store in a refrigerator (2–8 °C). Do not freeze.
Diluted solution: do not store at temperatures above 25°C. Do not store in a
refrigerator. Do not freeze.
The solution should be clear to slightly opalescent, colourless to slightly yellow.
The doctor will inspect the solution before administration and discard it if particles or discoloration are observed.

6. Contents of the pack and other information

What Biwalirudyna 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 of solution contains 50 mg of bivalirudin.
• After dilution (mixing 5 ml of reconstituted solution into an infusion bag [with a total volume of 50 ml] containing glucose solution or sodium chloride solution), 1 ml of solution contains 5 mg of bivalirudin.

Other ingredients: mannitol (E 421) and sodium hydroxide (to adjust pH within the range of 4.5 - 5.5).

What Biwalirudyna Accord looks like and contents of the pack
Biwalirudyna Accord is a powder for solution for injection/infusion (powder for concentrate solution).
Biwalirudyna Accord is a white or almost white powder in a glass vial.
Biwalirudyna Accord is available in cardboard packs containing 1, 5 or 10 vials.
Not all pack sizes may be marketed.

Marketing Authorisation Holder:
Accord Healthcare Polska Sp. z o.o.
Taśmowa Street 7
02-677 Warsaw
Tel: +48 22 577 28 00

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

This medicinal product is authorised in 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 full product information contained in the Summary of Product Characteristics.
Biwalirudyna Accord is indicated as an antithrombotic agent for use in adult patients undergoing percutaneous coronary intervention (PCI), including patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI).
Biwalirudyna Accord is also indicated in adult patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) in whom urgent or early invasive treatment is planned.
Biwalirudyna Accord should be used in combination with acetylsalicylic acid and clopidogrel.

Preparation
Biwalirudyna Accord must be prepared and administered under aseptic conditions.
Add 5 mL of sterile water for injections to one vial and gently rotate the vial until the product is completely dissolved and the solution becomes clear.
Withdraw 5 mL of solution from the vial and further dilute it in a total volume of 50 mL of 5% glucose for injection or 9 mg/mL (0.9%) sodium chloride solution for injection to achieve a final biwalirudin concentration of 5 mg/mL.
The reconstituted/ diluted solution should be inspected visually for particulate matter or discoloration. Do not use solutions that contain particulate matter or have changed color.
The reconstituted/ diluted solution should be clear or slightly opalescent, colorless to yellowish.

Reconstitution of concentrate for injection or infusion.
After reconstitution, the solution at a concentration of 50 mg/mL has a pH between 4.6 and 6.0 and an osmolality of 250 to 450 mOsm/kg.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Pharmaceutical incompatibilities
The following drugs must not be administered through the same intravenous line as biwalirudin, as this may cause cloudiness, formation of micro-particles, or large precipitates: alteplase, amiodarone hydrochloride, amphotericin B, chlorpromazine hydrochloride, diazepam, prochlorperazine edisylate, reteplase, streptokinase, and vancomycin hydrochloride.

The following six medicinal products exhibit concentration/dose-dependent incompatibility with biwalirudin. For details on concentrations showing compatibility or incompatibility, see section 6.2. Medicinal products incompatible with biwalirudin at higher concentrations are: dobutamine hydrochloride, famotidine, haloperidol lactate, labetalol hydrochloride, lorazepam, and promethazine hydrochloride.

Contraindications
Biwalirudyna Accord is contraindicated in patients:

• with known hypersensitivity to the active substance or to any of the excipients listed in section 6.1, or to hirudin
• with active bleeding or increased risk of bleeding due to coagulation disorders and (or) irreversible coagulation abnormalities
• with severe, uncontrolled hypertension
• with subacute bacterial endocarditis
• with severe renal impairment (GFR < 30 mL/min) and in dialyzed patients (see Summary of Product Characteristics, section 4.3)

Dosage
Patients undergoing percutaneous coronary intervention (PCI), including patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI
The recommended dose of biwalirudin for patients undergoing PCI is 0.75 mg/kg body weight as an intravenous bolus, immediately followed by continuous intravenous infusion at 1.75 mg/kg/hour for the duration of the procedure. The infusion may be continued at 1.75 mg/kg/hour for up to 4 hours after completion of PCI, followed by a reduced dose of 0.25 mg/kg/hour for an additional 4 to 12 hours, if clinically justified. In patients with ST-segment elevation myocardial infarction (STEMI), the infusion at 1.75 mg/kg/hour should be continued for up to 4 hours after completion of PCI, followed by a reduced dose of 0.25 mg/kg/hour for an additional 4 to 12 hours, if clinically justified (see section 4.4).
Patients who have undergone primary percutaneous coronary intervention (pPCI) should be carefully monitored for subjective and objective signs of myocardial ischemia.

Patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI)
The recommended initial dose of biwalirudin in patients with acute coronary syndrome (ACS) managed medically is 0.1 mg/kg body weight as an intravenous bolus, followed by continuous intravenous infusion at 0.25 mg/kg/hour. Patients requiring continued treatment may receive biwalirudin infusion at 0.25 mg/kg/hour for up to 72 hours.

If a medically treated patient is scheduled for PCI, an additional intravenous bolus dose of biwalirudin 0.5 mg/kg body weight should be administered before the procedure, followed by an infusion of 1.75 mg/kg/hour during the procedure. After PCI, the dose may be reduced to 0.25 mg/kg/hour for 4 to 12 hours, if clinically justified.

In patients scheduled for coronary artery bypass grafting (CABG) without cardiopulmonary bypass, biwalirudin infusion should be continued up to the time of surgery. Before surgery, administer a bolus dose of 0.5 mg/kg body weight, followed by continuous infusion at 1.75 mg/kg/hour during the procedure.

In patients scheduled for CABG with cardiopulmonary bypass, biwalirudin infusion should be continued until 1 hour before surgery. The infusion should then be stopped and unfractionated heparin (UFH) administered.

To ensure appropriate delivery of biwalirudin, the fully dissolved, reconstituted, and diluted product should be thoroughly mixed before administration (see section 6.6). The intravenous bolus injection should be administered promptly and decisively to ensure that the full bolus dose reaches the patient before the start of the procedure.

Intravenous lines should be primed with biwalirudin to ensure continuity of infusion after administration of the bolus dose.
Infusion should be initiated immediately after the bolus dose to ensure that the patient receives continuous infusion before and throughout the procedure.
The safety and efficacy of administering a bolus dose of biwalirudin without subsequent infusion have not been established and are not recommended, even for short PCI procedures.

Activated clotting time (ACT) may be used as a parameter to confirm that the patient has received biwalirudin.

Renal impairment
Biwalirudyna Accord is contraindicated in patients with severe renal impairment (GFR < 30 mL/min) and in dialyzed patients (see section 4.3).
In patients with mild or moderate renal impairment treated for ACS, the dose (0.1 mg/kg intravenous bolus / 0.25 mg/kg/hour infusion) does not need to be adjusted.
In patients with moderate renal impairment (glomerular filtration rate GFR 30–59 mL/min) undergoing PCI (regardless of whether they received biwalirudin for ACS or not), the infusion rate should be reduced to 1.4 mg/kg/hour. The intravenous bolus dose should remain unchanged as specified for ACS or PCI dosing.

Hepatic impairment
Dose adjustment is not necessary.
(For complete dosage information, see Summary of Product Characteristics, section 4.2)

Shelf life
3 years

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for up to 24 hours when stored at 2–8°C. Store in a refrigerator (2–8°C). Do not freeze. From a microbiological point of view, unless the method of opening/reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, the user is responsible for the duration and conditions of storage prior to use.

Diluted solution: Chemical and physical in-use stability has been demonstrated for up to 24 hours when stored at 25°C.
Do not store above 25°C. Do not store in a refrigerator. Do not freeze.
From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, the user is responsible for the duration and conditions of storage prior to use.