Prospect: information for the user

Bivalirudin Sandoz 250mg powder for concentrate for injectable solution or for infusion EFG

Bivalirudin

Read this prospect carefully before starting to use this medicine, because it contains important information for you.

• Keep this prospect, as you may need to read it again.
• If you have any doubts, consult your doctor.
• This medicine has been prescribed to you alone, and you must not give it to other people even if they have the same symptoms as you, as it may harm them.
• If you experience adverse effects, consult your doctor, even if they do not appear in this prospect. See section 4.

1. What isBivalirudin Sandozand for what it is used

2. What you need to know before starting to useBivalirudin Sandoz

3. How to useBivalirudin Sandoz

4. Possible adverse effects

5. Storage ofBivalirudin Sandoz

6. Contents of the package and additional information

Bivalirudina Sala contains a substance called bivalirudin that is an antithrombotic medication. Antithrombotics are medications that prevent the formation of blood clots (thrombosis).

Bivalirudina Sala is used to treat patients:

• with chest pain due to heart disease (acute coronary syndromes - ACS)
• who are to undergo surgery to treat blockage of blood vessels (angioplasty and/or percutaneous coronary intervention – PCI).

No use Bivalirudina Sala

• If you are allergic to bivalirudin or any of the other components of this medication (listed in section 6) or to hirudins (other anticoagulant medications).
• If you experience or have recently experienced bleeding in the stomach, intestines, bladder, or other organs, for example, if you have observed blood in your stool or urine (except for 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. Consult your doctor if in doubt.

Warnings and Precautions

Consult your doctor before using Bivalirudina Sala

• If bleeding occurs (in case of bleeding, treatment with Bivalirudina Sala will be suspended). During treatment, your doctor will monitor you for signs of bleeding.
• If you have previously received treatment with medications 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 rare (affect between 1 and 10 users out of every 1,000).
• If you are receiving radiation therapy in the blood vessels that supply blood to the heart (treatment called brachytherapy with beta or gamma radiation).

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

Children and Adolescents

• If you are a child (under 18 years old), this medication is not suitable for you.

Use of Bivalirudina Sala with Other Medications

Inform your doctor:

• If you are using, have used recently, or may use other medications
• If you are taking blood thinners or medications that prevent blood clot formation (anticoagulants or antithrombotics, e.g., warfarin, dabigatran, apixaban, rivaroxaban, acetylsalicylic acid, clopidogrel, prasugrel, ticagrelor).

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

Pregnancy and Breastfeeding

If you are pregnant or breastfeeding, or if you think you may be pregnant or plan to become pregnant, consult your doctor before using this medication.

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

Driving and Operating Machinery

It is known that the effects of this medication 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 operate machinery.

Bivalirudina Sala contains sodium

This medication contains less than 23 mg of sodium per vial, making it essentially "sodium-free".

Your treatment with Bivalirudina Sala will be supervised by a doctor. The doctor will decide how much Bivalirudina Sala you will receive and prepare the medication.

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

Dose

For patients with acute coronary syndrome (ACS) receiving medical treatmenttherecommended initial dose is:

• 0.1 mg/kgof body weight administered via intravenous injection, followed by an infusion (drip) in a vein, of 0.25 mg/kg of body weight/hour for up to 72 hours.

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

• 0.5 mg/kgof body weight administered via intravenous injection, followed by an infusion in a vein of1.75 mg/kgof body 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 be returned to0.25 mg/kgof body weight/hour.

If you need to undergo coronary artery bypass surgery, or the treatment with bivalirudina is interrupted one hour before the intervention or an additional dose of 0.5 mg/kg body weight is administered via injection, followed by an infusion of 1.75 mg/kg body weight/hour.

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

• 0.75 mg/kgof body weight administered via injection, followed immediately by an infusion of1.75 mg/kgof body 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 individuals, if renal function is observed to decrease, it may be necessary to reduce the dose.

The 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 disease.

If you receive more Bivalirudina Sala than you should

Your doctor will decide how to treat you, and this includes when to discontinue the medication and monitor you for signs of adverse effects.

If you have any other questions about the use of this medication, ask your doctor.

Like all medicines, this medicine can cause side effects, although not everyone experiences them. If you experience any of the following serious side effects:

• while in the hospital: inform your doctor or nurse immediately
• after leaving the hospital: contact your doctor directly or go immediately to the nearest emergency department of your hospital

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

• Bleeding and hematoma at the injection site (after ICP treatment) that may be painful. Infrequently, this may require surgical repair of the blood vessel in the groin (fistula, pseudoaneurysm) (may affect 1 in 1000 people). Infrequently (may affect 1 in 100 people), it may decrease platelet count, which may worsen bleeding. Bleeding in the gums (infrequent, may affect 1 in 100 people) is usually not severe.

• Allergic reactions are infrequent (may affect up to 1 in 100 people) and are usually not severe, although they may be severe in some circumstances and, in rare cases, may be fatal due to low blood pressure (shock). Initially, symptoms may be limited, such as itching, skin redness, rash, or small bumps on the skin.

In some cases, reactions may be more severe with throat itching, throat constriction, facial swelling, tongue, or lip swelling, high-pitched sound when inhaling (stridor), difficulty breathing, or difficulty exhaling.

• Thrombosis (blood clot), a side effect that is infrequent (may affect up to 1 in 100 people) and may result in severe 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 which may also be fatal) and/or catheter thrombosis, both of which are rare (may affect 1 in 1000 people).

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

• while in the hospital: inform your doctor or nurse
• after leaving the hospital: first visit your doctor. If not possible, go immediately to the nearest emergency department of your hospital

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

• Minor bleeding

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

• Anemia (low red blood cell count)
• Hematoma (bruise)

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

• Nausea (feeling unwell) and/or vomiting (feeling sick)

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

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

Reporting side effects

If you experience any type of side effect, consult your doctor, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly to theSpanish System for Pharmacovigilance of Medicines for Human Use:www.notificaRAM.es

By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

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

Do not use this medication after the expiration date that appears on the box after CAD. The expiration date is the last day of the month indicated.

Lyophilized powder: This medication does not require special storage conditions.

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

Diluted solution: Chemical and physical stability in use has been demonstrated for 24 hours at 25°C. Do not store at a temperature above 25°C. Do not freeze.

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

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

The solution must be transparent to slightly opalescent, colorless to slightly yellowish.

The doctor will inspect the solution and discard it if it contains particles or is discolored.

Composition of Bivalirudin Sandoz

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

The other components are mannitol and sodium hydroxide (to adjust the pH).

Appearance of Bivalirudin Sandoz and contents of the pack

Bivalirudin Sandoz is a powder for concentrate for solution for injection or for infusion (powder for concentrate).

Bivalirudin Sandoz is a white to light yellowish powder in a glass vial.

Bivalirudin Sandoz is available in packs containing 2 or 10 vials.

Marketing Authorization Holder and Responsible Person

Laboratorio Reig Jofré, S.A.

C/ Gran Capitán, 10

08970 Sant Joan Despí (Barcelona)

Spain

Last review date of this leaflet: November 2020

The detailed and updated information on this medicinal product is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS):http://www.aemps.gob.es/

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The following information is directed only to healthcare professionals:

Healthcare professionals should consult the Product Information for complete information to prescribe this medicinal product.

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

Bivalirudin Sandoz is also indicated for the treatment of adult patients with unstable angina/myocardial infarction without ST-segment elevation (UA/NSTEMI) who are to be treated urgently or early.

Bivalirudin Sandoz should be administered together with aspirin and clopidogrel.

Preparation Instructions

Procedures should be carried out aseptically for the preparation and administration of Bivalirudin Sandoz.

Add 5 ml of sterile water for injection to a vial of Bivalirudin Sandoz and agitate gently until the powder is completely dissolved and the solution is transparent.

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

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

The reconstituted/diluted solutions should be transparent or slightly opalescent, colorless or slightly yellowish.

The disposal of unused medicinal product and all materials that have been in contact with it should be carried out in accordance with local regulations.

Incompatibilities

The following medicinal products should not be administered through the same intravenous line as bivalirudin, as they may cause the formation of turbidity, the formation of microparticles or precipitation: alteplase, amiodarone hydrochloride, amphotericin B, chlorpromazine hydrochloride, diazepam, prochlorperazine edisilate, reteplase, streptokinase and vancomycin hydrochloride.

The following six medicinal products show incompatibilities of concentration of dose with bivalirudin. In Section 6.2, the compatible and incompatible concentrations of these medicinal products are summarized. The medicinal products incompatible with bivalirudin at higher concentrations are: dobutamine hydrochloride, famotidine, haloperidol lactate, labetalol hydrochloride, lorazepam and promethazine hydrochloride.

Contraindications

Bivalirudin Sandoz is contraindicated in patients with:

• known hypersensitivity to the active ingredient or to any of the excipients of the product included in Section 6.1, or to hirudins.
• active bleeding or high risk of bleeding due to haemostasis disorders and/or irreversible coagulation disorders.
• uncontrolled severe hypertension
• subacute bacterial endocarditis.
• severe renal insufficiency (glomerular filtration rate <30)

Dosage

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

The recommended dose of bivalirudin 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 prolonged up to a maximum of 4 hours after the PCI, and continued at a reduced infusion rate of 0.25 mg/kg/h for 4 to 12 hours, if clinically necessary.

Patients should be closely monitored after PCI for signs and symptoms consistent with myocardial ischaemia.

Patients with unstable angina/myocardial infarction without ST-segment elevation (UA/NSTEMI)

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

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

After PCI, the reduced infusion rate 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 a cardiopulmonary bypass pump, the intravenous infusion of bivalirudin should be continued until the time of surgery. Just 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 a cardiopulmonary bypass pump, the intravenous infusion of bivalirudin should be continued until 1 hour before surgery, after which the infusion should be interrupted and the patient treated with unfractionated heparin (UFH).

To ensure the appropriate administration of bivalirudin, the reconstituted and fully diluted product should be mixed well before administration (see Section 6.6). The bolus dose should be administered as an intravenous bolus to ensure that the entire bolus reaches the patient before the procedure begins.

The intravenous infusion lines should be primed with bivalirudin to ensure the continuous infusion of the medicinal product after the bolus administration.

The infusion rate should be initiated immediately after the bolus administration to ensure that it reaches the patient before the procedure begins, and should continue uninterrupted during the procedure. The safety and efficacy of a bolus dose of bivalirudin without subsequent infusion have not been evaluated, and is not recommended even if a short PCI procedure is planned.

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

Renal insufficiency

Bivalirudin Sandoz is contraindicated in patients with severe renal insufficiency (glomerular filtration rate <30)

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

Patients with moderate renal insufficiency (glomerular filtration rate 30-59 ml/min) who are to undergo PCI (whether or not treated with bivalirudin for ACS) should receive a lower infusion rate of 1.4 mg/kg/h. The bolus dose should not be modified from the dosing described under ACS or PCI.

Liver insufficiency

No adjustment of the dose is required.

(For complete information on dosage, see Section 4.2 of the Product Information)

Shelf-life

30 months

Concentrated reconstituted solution: chemical and physical stability has been demonstrated for 24 hours at 2-8°C. Store in 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 at a temperature above 25°C. Do not freeze.

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

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