BIVALIRUDINA SALA 250 mg POWDER FOR CONCENTRATE FOR INJECTION OR INFUSION SOLUTION

2. What you need to know before you use Bivalirudina Sala

Do not use Bivalirudina Sala

• if you are allergic to bivalirudina or any of the other ingredients of this medicine (listed in section 6) or to hirudins (other anticoagulant medicines).
• if you have recently had or are currently experiencing bleeding in the stomach, intestine, bladder or other organs, for example, if you have seen blood in your stools or urine (except in the case of menstrual bleeding).
• if you have or have had blood clotting problems (low platelet count).
• if you have severe high blood pressure.
• if you have a heart tissue infection.
• if you have severe kidney problems or if you need dialysis. If in doubt, consult your doctor.

Warnings and precautions

Talk to your doctor before using Bivalirudina Sala

• if bleeding occurs (in case of bleeding, treatment with Bivalirudina Sala will be stopped). During treatment, your doctor will monitor you for signs of bleeding.
• if you have previously been treated with medicines similar to Bivalirudina Sala (e.g. lepirudin).
• before starting the injection or infusion, your doctor will inform you about the signs of allergic reactions. These reactions are uncommon (affect 1 to 10 users in 1,000).
• if you are receiving radiation therapy in the blood vessels that supply the heart (treatment called brachytherapy with beta or gamma radiation).

After treatment of a cardiac episode with Bivalirudina Sala, you should remain in the hospital for at least 24 hours and should be monitored for any symptoms or signs similar to those experienced during the cardiac episode that led to your hospitalization.

Children and adolescents

Using Bivalirudina Sala with other medicines

Tell your doctor:

These medicines may increase the risk of side effects, such as bleeding, if administered at the same time as Bivalirudina Sala. Bivalirudina Sala may affect the results of warfarin blood tests (INR test).

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using this medicine.

Bivalirudina Sala should not be used during pregnancy unless clearly necessary. Your doctor will consider whether treatment is appropriate for you. If you are breastfeeding, your doctor will decide whether the use of Bivalirudina Sala is appropriate in your case.

Driving and using machines

The effects of this medicine are short-term. Bivalirudina Sala is only administered when the patient is in the hospital. Therefore, it is unlikely to affect your ability to drive or use machines.

Bivalirudina Sala contains sodium

This medicine contains less than 23 mg of sodium per vial, so it is essentially "sodium-free".

3. How to use Bivalirudina Sala

Your treatment with Bivalirudina Sala will be supervised by a doctor. The doctor will decide how much Bivalirudina Sala to administer and prepare the medicine.

The dose you receive depends on your weight and the type of treatment you receive.

Dose

For patients with acute coronary syndrome (ACS) who receive medical treatmentthe initial doserecommended is:

• 0.1 mg/kgbody weight by intravenous injection, followed by an infusion (drip) in the vein, of 0.25 mg/kgbody weight/hour for up to 72 hours.

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

• 0.5 mg/kgbody weight by intravenous injection, followed by an infusion in the vein of 1.75 mg/kgbody weight/hour for at least the duration of the PCI. This intravenous infusion may continue for up to 4 hours.

• When this treatment ends, the infusion may return to 0.25 mg/kgbody weight/hour.

If you need to undergo coronary artery bypass grafting, either the treatment with bivalirudina will be stopped one hour before the intervention or an additional dose of 0.5 mg/kg body weight will be administered by injection, followed by an infusion of 1.75 mg/kg body weight/hour.

For patients who start with a percutaneous coronary intervention (PCI)the recommended dose is:

• 0.75 mg/kgbody weight by injection, followed immediately by an infusion of 1.75 mg/kgbody weight/hour (the intravenous infusion may continue for up to 4 hours).

If you have kidney problems, it may be necessary to reduce the dose of Bivalirudina Sala.

In elderly people, if there is a decrease in kidney function, it may be necessary to reduce the dose.

Your doctor will decide the duration of your treatment.

Bivalirudina Sala is only for injection, followed by an infusion (drip), in a vein (never in a muscle). It is administered and supervised by an experienced doctor in the treatment of patients with heart diseases.

If you receive more Bivalirudina Sala than you should

Your doctor will decide how to treat you, including when to stop the medicine and monitor you for signs of side 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 experience any of the following side effects, potentially serious:

• while you are in the hospital: tell your doctor or nurse immediately
• after you leave the hospital: contact your doctor directly or go immediately to the emergency department of your nearest hospital

The most common (affecting up to 1 in 10 people) and important side effect of treatment with Bivalirudina Sala is major bleeding, which can occur anywhere in the body (e.g. stomach, digestive system (including vomiting blood or blood in the stools), abdomen, lungs, groin, bladder, heart, eyes, ears, nose or brain). Rarelyit can cause a stroke or be fatal. Swelling or pain in the groin or arm, back pain, bruising, headache, coughing up blood, pink or red urine, sweating, dizziness, fainting or nausea due to low blood pressure can all be signs of internal bleeding. It is more likely to occur if Bivalirudina Sala is used in combination with other anticoagulants or antithrombotics (see section 2 'Using Bivalirudina Sala with other medicines').

• Bleeding and hematoma at the injection site (after PCI treatment) can be painful. Rarely (affecting 1 in 1,000 people) this may require surgical repair of the blood vessel in the groin (fistula, pseudoaneurysm). Uncommonly (affecting 1 in 100 people) it can decrease the platelet count, which can worsen bleeding. Bleeding in the gums (uncommon, affecting 1 in 100 people) is usually not serious.

• Allergic reactions are uncommon (affecting up to 1 in 100 people) and are normally not serious, although they can be serious in some circumstances and rarely can be fatal due to low blood pressure (shock). Initially, the symptoms can be limited, such as itching, redness of the skin, rash or small bumps on the skin.

Occasionally, reactions can be more severe with itching of the throat, throat tightness, swelling of the eyes, face, tongue or lips, high-pitched sound when inhaling (stridor), difficulty breathing or difficulty exhaling.

• Thrombosis (blood clot), an uncommon side effect (affecting up to 1 in 100 people) that can result in serious or fatal complications such as a heart attack. Thrombosis includes coronary artery thrombosis (blood clot in the heart arteries or within a stent that resembles a heart attack, and can also be fatal) and/or catheter thrombosis, both are rare (affecting 1 in 1,000 people).

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

• while you are in the hospital: tell your doctor or nurse
• after you leave the hospital: first contact your doctor. If this is not possible, 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 (low red blood cell count)
• Bruising (haematoma)

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

• Nausea (feeling sick) and/or vomiting

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

• Increased INR test values (warfarin blood test results) (see section 2, Other medicines and Bivalirudina Sala)
• Angina or chest pain
• Slow heart rate
• Fast heart rate
• Difficulty breathing
• Reperfusion injury (slow or absent reflow): poor circulation in the heart arteries after reopening

Reporting of side effects

If you experience any side effects, talk to your doctor, even if they are not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es

By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Bivalirudina Sala

Since Bivalirudina Sala is a medicine for use only in the hospital setting, healthcare professionals are responsible for its storage.

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 carton after EXP. The expiry date is the last day of the month shown.

Lyophilised powder: This medicine does not require any special storage conditions.

Reconstituted solution: The chemical and physical in-use stability has been demonstrated for 24 hours at a temperature between 2-8°C. Store in a refrigerator (between 2°C and 8°C). Do not freeze.

Diluted solution: The chemical and physical in-use stability has been demonstrated for 24 hours at 25°C. Do not store above 25°C. 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 in-use storage times and conditions are the responsibility of the user.

The solution should be clear to slightly opalescent, colourless to slightly yellowish.

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

6. Container Contents and Additional Information

Composition of Bivalirudina Sala

• The active ingredient is bivalirudina.
• Each vial contains 250 mg of bivalirudina.
• After reconstitution (addition of 5 ml of sterile water for injectable preparations to the vial to dissolve the powder), 1 ml contains 50 mg of bivalirudina.
• After dilution (mixing 5 ml of the reconstituted solution in an infusion bag of glucose solution or sodium chloride solution [total volume 50 ml]), 1 ml contains 5 mg of bivalirudina.

The other components are mannitol and sodium hydroxide (for pH adjustment).

Appearance of Bivalirudina Sala and Container Contents

Bivalirudina Sala is a powder for concentrate for solution for injection or infusion (powder for concentrate).

Bivalirudina Sala is a white to off-white powder in a glass vial.

Bivalirudina Sala is available in packs containing 2 or 10 vials.

Marketing Authorization Holder and Manufacturer

Laboratorio Reig Jofré, S.A.

C/ Gran Capitán, 10

08970 Sant Joan Despí (Barcelona)

Spain

Date of Last Revision of this Leaflet: November 2020

Detailed and updated information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS): http://www.aemps.gob.es/

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The following information is intended for healthcare professionals only:

Healthcare professionals should consult the Summary of Product Characteristics for complete information to prescribe this medicinal product.

Bivalirudina Sala is indicated as an anticoagulant in adult patients undergoing percutaneous coronary intervention (PCI), including patients with ST-segment elevation myocardial infarction undergoing primary PCI.

Bivalirudina Sala is also indicated for the treatment of adult patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) who are to be undergoing urgent or early intervention.

Bivalirudina Sala should be administered in combination with acetylsalicylic acid and clopidogrel.

Preparation Instructions

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

Add 5 ml of sterile water for injectable preparations to a vial of Bivalirudina Sala and gently shake until completely dissolved and the solution is clear.

Withdraw 5 ml from the vial and further dilute to a total volume of 50 ml with 5% glucose solution or 0.9% sodium chloride solution to obtain a final concentration of bivalirudina of 5 mg/ml.

The reconstituted/diluted solution should be visually inspected for particles and any possible alteration of the solution color. Solutions containing particles should not be used.

The reconstituted/diluted solutions should be clear to slightly opalescent, colorless to slightly yellowish.

Disposal of unused medicinal product and all materials that have come into contact with it should be done in accordance with local regulations.

Incompatibilities

The following medicinal products should not be administered through the same intravenous line as bivalirudina, as they may cause turbidity, microparticle formation, or precipitation: alteplase, amiodarone hydrochloride, amphotericin B, chlorpromazine hydrochloride (HCl), diazepam, prochlorperazine edisylate, reteplase, streptokinase, and vancomycin hydrochloride.

The following six medicinal products show concentration-related incompatibilities with bivalirudina. The compatible and incompatible concentrations of these medicinal products are summarized in Section 6.2. The medicinal products that are incompatible with bivalirudina at higher concentrations are: dobutamine hydrochloride, famotidine, haloperidol lactate, labetalol hydrochloride, lorazepam, and promethazine HCl.

Contraindications

Bivalirudina Sala is contraindicated in patients with:

• known hypersensitivity to the active substance or to any of the excipients listed in Section 6.1, or to hirudins.
• active bleeding or high risk of bleeding due to hemostatic disorders and/or irreversible coagulation disorders.
• uncontrolled severe hypertension
• subacute bacterial endocarditis.
• severe renal impairment (glomerular filtration rate <30 ml min) and in patients dependent on dialysis. (see section 4.3 of the summary product characteristics)< li>

Posology

Patient undergoing percutaneous coronary intervention (PCI), including primary PCI

The recommended dose of bivalirudina in 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/h for at least the duration of the procedure. If clinically justified, the infusion of 1.75 mg/kg body weight/h may be extended up to a maximum of 4 hours after PCI, and continued at a reduced infusion dose of 0.25 mg/kg/h for 4-12 hours, if clinically necessary.

Patient should be carefully monitored after PCI for signs and symptoms consistent with myocardial ischemia.

Patient with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI)

The recommended initial dose of bivalirudina in 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 treated may continue the infusion of 0.25 mg/kg/h for up to 72 hours.

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

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

For patients undergoing coronary artery bypass grafting (CABG) without cardiopulmonary bypass, bivalirudina infusion should be continued until the time of surgery. Immediately before surgery, a bolus dose of 0.5 mg/kg should be administered followed by an intravenous infusion of 1.75 mg/kg/h during surgery.

For patients undergoing CABG with cardiopulmonary bypass, bivalirudina infusion should be continued until 1 hour before surgery, after which the infusion should be discontinued and the patient should be treated with unfractionated heparin (UFH).

To ensure adequate administration of bivalirudina, the reconstituted and fully diluted product should be well mixed before administration (see Section 6.6). The bolus dose should be administered as a rapid intravenous bolus to ensure that the complete bolus is delivered to the patient before the start of the procedure.

Intravenous infusion lines should be primed with bivalirudina to ensure continuity of drug infusion after bolus administration.

The infusion dose should be started immediately after bolus administration to ensure that it is delivered to the patient before the procedure, and should be continued uninterrupted for the duration of the procedure. The safety and efficacy of a bivalirudina bolus dose without subsequent infusion have not been evaluated and are not recommended, even if a short PCI procedure is planned.

An increase in activated clotting time (ACT) may serve as an indicator that the patient has received bivalirudina.

Renal Impairment

Bivalirudina Sala is contraindicated in patients with severe renal impairment (glomerular filtration rate <30 ml min) and in patients undergoing dialysis (see section 4.3).< p>

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

Patient with moderate renal impairment (GFR 30-59 ml/min) who are to undergo PCI (whether or not they are treated with bivalirudina for ACS) should receive a lower infusion rate of 1.4 mg/kg/h. The bolus dose should not be modified from the posology described under ACS or PCI.

Hepatic Impairment

No dose adjustment is needed.

(For complete information on posology, see Section 4.2 of the Summary of Product Characteristics)

Shelf Life

30 months

Reconstituted concentrated solution: chemical and physical stability has been demonstrated for 24 hours at 2-8°C. Store in a refrigerator (between 2 and 8°C). Do not freeze.

Diluted solution: chemical and physical stability has been demonstrated for 24 hours at 25°C. Do not store above 25°C. Do not freeze.

From a microbiological point of view, unless the opening/reconstitution/dilution method precludes the risk of microbial contamination, the product should be used immediately.

If not used immediately, the in-use storage times and conditions are the responsibility of the user.