Bivalirudin Hikma: detailed information

Package leaflet: Information for the user

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

bivalirudin
Generic medicine
Please 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 questions, ask your doctor, pharmacist or nurse.
If you get any side effects, including any not listed in this leaflet, tell your doctor. See section 4.

Contents of this leaflet:

What Bivalirudin Hikma is and what it is used for
What you need to know before you use Bivalirudin Hikma
How to use Bivalirudin Hikma
Possible side effects
How to store Bivalirudin Hikma
Contents of the pack and other information

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

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

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

2. What you need to know before using Bivalirudina Hikma

Do not use Bivalirudina Hikma

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 menstrual period).
if you currently have, or have had, coagulation disorders (low platelet count).
if you have high blood pressure.
if you have an infection of the heart tissue.
if you have severe kidney problems or require dialysis.

Consult your doctor if you have any doubts.
Warnings and precautions
Talk to your doctor before using Bivalirudina Hikma

if you experience any bleeding (if this occurs, treatment with Bivalirudina Hikma 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 Bivalirudina Hikma (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 up to 1 out of 100 people).
if you are currently undergoing radiation therapy in the blood vessels supplying the heart (a treatment called beta or gamma brachytherapy).

After being treated with Bivalirudina Hikma for a heart condition, you must remain in hospital for at least 24 hours and be monitored for any symptoms or signs suggestive of the heart problem for which you were admitted.
Children and adolescents

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

Other medicines and Bivalirudina Hikma
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 Bivalirudina Hikma. Bivalirudina Hikma may alter blood test results used to monitor warfarin (INR test).
Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, planning to become pregnant, or are breastfeeding, ask your doctor for advice before taking this medicine.
Bivalirudina Hikma 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 Bivalirudina Hikma should be used.
Driving and using machines
The effects of this medicine are known to be short-lived. Bivalirudina Hikma is administered only when a patient is in hospital. Therefore, it is unlikely to affect your ability to drive or operate machinery.
Bivalirudina Hikma contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e. essentially ‘sodium-free’.

3. How to use Bivalirudina Hikma

Treatment with Bivalirudina Hikma will be supervised by a doctor. The doctor will decide the amount of
Bivalirudina Hikma 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 of 0.25 mg/kg body weight per hour for up to 72 hours.

If, after this dose, you need to 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 for coronary artery bypass graft surgery, bivalirudin therapy should be discontinued one hour before surgery, or you may be given an additional dose of 0.5 mg/kg body weight by injection, followed by an infusion of 1.75 mg/kg body weight per hour for the duration of the procedure.
For patients starting with a percutaneous coronary intervention (PCI), the recommended dose is:

0.75 mg/kg body weight as an intravenous injection, immediately followed by an intravenous infusion of 1.75 mg/kg body weight/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 a reduced infusion dose of 0.25 mg/kg body weight for an additional 4–12 hours.

The dose of Bivalirudina Hikma may be reduced if you have renal problems.
In elderly patients with impaired renal function, dose reduction may be necessary.
Your doctor will decide the duration of your treatment.
Bivalirudina Hikma is administered by injection followed by infusion (intravenous infusion) 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 Bivalirudina Hikma than you should
Your doctor will decide how to manage you, including discontinuation of the medicine 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 one of the following side effects, which could be potentially serious:
o if you are in hospital: inform your doctor or nurse immediately,
o after leaving hospital: contact your doctor straight away or go immediately to the
nearest hospital Emergency Department

The most common serious side effect (may occur in up to 1 in 10 people) of treatment with Bivalirudina Hikma is major bleeding, which can occur anywhere in the body (e.g. stomach, gastrointestinal tract (including vomiting blood or blood in faeces), 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 Bivalirudina Hikma is used in combination with other anticoagulant or antiplatelet medicines (see section 2 “Taking other medicines”).

Bleeding and bruising at the injection site (after PCI treatment) may be painful. In rare cases, surgical intervention may be required to repair the 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 severe, but 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 lumps. 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 when breathing in (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 potentially fatal 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 may be 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 serious):
o if you are in hospital: inform your doctor or nurse
o after leaving hospital: try contacting your doctor first. If you cannot contact your doctor, go immediately to the nearest hospital Emergency Department

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 (feeling sick)

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 Hikma”)
Angina or chest pain
Slowing of the heartbeat
Fast heartbeat
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 get any side effects, 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 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 Bivalirudina Hikma

Since Bivalirudina Hikma is a medicinal product intended exclusively for hospital use, the storage of Bivalirudina Hikma is the responsibility of healthcare professionals.
Keep this medicinal product out of the sight and reach of children.
Do not use this medicinal product after the expiry date stated on the label and carton following “EXP.”.
The expiry date refers to the last day of that month.
Lyophilised powder: do not store above 25°C.
Reconstituted solution: store in a refrigerator (2°C – 8°C). Do not freeze.
Diluted solution: do not store above 25°C. Do not freeze.
The solution should range in appearance from clear to slightly opalescent and from colourless to slightly yellow. The doctor will check the solution and discard it if it contains particles or is discoloured.

6. Package contents and other information

What Bivalirudina Hikma 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 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 components are mannitol, sodium hydroxide.

Description of the appearance of Bivalirudina Hikma and package contents
Bivalirudina Hikma is a powder for concentrate for solution for injection/infusion (powder for concentrate).
Bivalirudina Hikma is a white to off-white powder in a glass vial.
Bivalirudina Hikma is available in boxes containing 10 vials.

Marketing Authorization Holder
Hikma Farmacêutica (Portugal) S.A.
Estrada Rio da Mó, 8, 8A and 8B – Fervença
2705-906 Terrugem SNT, Portugal
Tel.: +351 219608453
e-mail: [email protected]

Manufacturer
Quercus Labo
Wijmenstraat 21p,
Mariakerke, 9030,
Belgium

The following information is intended exclusively for healthcare professionals:

Healthcare professionals should consult the Summary of Product Characteristics for complete prescribing information.
Bivalirudina Hikma 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.
Bivalirudina Hikma is also indicated for the treatment of adult patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) when undergoing urgent and immediate intervention.
Bivalirudina Hikma must be administered with acetylsalicylic acid and clopidogrel.

Instructions for Preparation
Aseptic techniques must be used for the reconstitution and administration of Bivalirudina Hikma.
Add 5 mL of sterile water for injections to a vial of Bivalirudina Hikma and gently shake until complete dissolution and a clear solution are obtained.
Withdraw 5 mL from the vial and further dilute in a total volume of 50 mL of 5% glucose injection solution or 9 mg/mL (0.9%) sodium chloride injection solution to achieve a final bivalirudin concentration of 5 mg/mL.
The reconstituted/diluted solution should be inspected visually for particulate matter and discoloration. Do not use solutions containing particulate matter.
The reconstituted/diluted solution will be a solution ranging from clear to slightly opalescent, colorless to slightly yellow.
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, as they may cause cloudiness, formation of microparticles, or coarse 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 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: hydrochloride dobutamine, famotidine, haloperidol lactate, hydrochloride labetalol, lorazepam, and promethazine HCl.

Contraindications
Bivalirudina Hikma is contraindicated in patients with:

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 dialysis-dependent patients (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 in patients undergoing PCI consists of an intravenous bolus of 0.75 mg/kg body weight, followed immediately by a continuous intravenous infusion 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 after PCI, and at a reduced rate 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 percutaneous coronary intervention and 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 of the SmPC).
Patients should be closely monitored after primary PCI to detect signs and symptoms consistent with myocardial ischemia.

Patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI)
The recommended initial dose of bivalirudin in patients receiving 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 pharmacological treatment may continue the infusion of 0.25 mg/kg/hour for up to 72 hours.
If patients receiving pharmacological treatment undergo PCI, an additional bolus of 0.5 mg/kg of bivalirudin should be administered before the procedure, and the infusion rate during the procedure should be increased to 1.75 mg/kg/hour.
After PCI, the reduced dose infusion of 0.25 mg/kg/hour may be resumed for 4 to 12 hours, if clinically necessary.

For patients undergoing off-pump aorto-coronary bypass surgery (CABG), the intravenous infusion of bivalirudin should be continued until the time of surgery. 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 aorto-coronary bypass surgery (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 mixed thoroughly 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 must be primed with bivalirudin to ensure continuity of drug infusion after bolus administration.
The infusion must be started immediately after administration of the bolus dose to ensure that the patient receives treatment before the procedure, and must be continued uninterrupted for the duration of the procedure. The safety and efficacy of a bolus dose of bivalirudin without subsequent infusion have not been evaluated and this is not recommended, even for short PCI procedures.

An increase in activated clotting time (ACT) may be used to confirm that a patient has received bivalirudin.

Renal impairment
Bivalirudina Hikma is contraindicated in patients with severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min) and in dialysis-dependent patients (see section 4.3).
The dose intended for ACS (0.1 mg/kg bolus and 0.25 mg/kg/hour infusion) should not be modified 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 modified compared to the dosage previously described for ACS or PCI.

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°C–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. Do not store above 25°C. Do not freeze.