AGRASTAT 0.25 mg/ml CONCENTRATE FOR INFUSION SOLUTION

2. What you need to know before you use AGRASTAT

Do not use AGRASTAT:

• If you are allergic (hypersensitive) to tirofiban or any of the other ingredients of AGRASTAT (listed in section 6).
• If you have internal bleeding or a history of internal bleeding in the last 30 days.
• If you have a history of intracranial bleeding, a brain tumor, or abnormal blood vessels in the brain.
• If you have severe uncontrolled high blood pressure (malignant hypertension).
• If you have a low platelet count (thrombocytopenia) or blood coagulation disorders.
• If you developed thrombocytopenia while being treated with AGRASTAT or another medicine of the same therapeutic group.
• If you have had a stroke in the last 30 days or any history of hemorrhagic stroke.
• If you have had major trauma or major surgery in the last six weeks.
• If you have severe liver failure.

Your doctor will review your medical history to see if you have a higher risk of experiencing side effects associated with the use of this medicine.

Warnings and precautions

Consult your doctor before starting to use AGRASTAT, if you have or have had:

• Any medical problem.
• Any allergy.
• Cardiopulmonary resuscitation, biopsy, or lithotripsy in the last 2 weeks.
• Major trauma or major surgery in the last 3 months.
• Stomach or intestine (duodenum) ulcer in the last 3 months.
• Recent bleeding disorder (in the last year) such as bleeding in the stomach or intestine, or blood in the urine or feces.
• Recent spinal intervention.
• History or symptoms of aortic rupture (aortic dissection).
• Uncontrolled hypertension.
• Inflammation of the membrane that surrounds the heart (pericarditis).
• Inflammation of the veins (active vasculitis).
• Problems in the blood vessels of the eye (retina).
• Problems with medicines that help prevent or dissolve blood clots.
• Kidney problems.
• Insertion of a special intravenous catheter under the collarbone in the last 24 hours.
• Heart failure.
• Low blood pressure due to heart failure (cardiogenic shock).
• Liver disorder.
• Low blood count or anemia.

Using AGRASTAT with other medicines:

In general, AGRASTAT can be used with other medicines. Please inform your doctor if you are taking, have recently taken, or might take any other medicines, including those without a prescription, as they may affect the action of these. It is very important that you inform your doctor if you are taking medicines that prevent the formation of clots, such as warfarin.

Using AGRASTAT with food, drinks, and alcohol

Food and drinks do not affect this medicine.

Pregnancy, breastfeeding, and fertility

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

Driving and using machines

Due to your condition, you will not be able to drive or operate machinery while using AGRASTAT.

AGRASTAT contains sodium

This medicine contains approximately 189 mg of sodium per 50 ml vial, which should be taken into account in the treatment of patients with low-sodium diets.

3. How to use AGRASTAT

AGRASTAT must be prescribed by qualified doctors with experience in the management of acute coronary syndromes.

AGRASTAT is administered intravenously. Your doctor will decide the appropriate dose, depending on your condition and weight.

Use in children

Use in children is not recommended.

If you use more AGRASTAT than you should

Your dose of AGRASTAT will be carefully monitored and supervised by your doctor and pharmacist.

The most commonly reported side effect of overdose was bleeding. If you notice bleeding, you should inform your doctor immediately.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone: 91 562 04 20, indicating the medicine and the amount ingested.

If you forget to use AGRASTAT

Your doctor will decide when to administer AGRASTAT.

If you stop using AGRASTAT

Your doctor will decide when treatment should be stopped. However, if you wish to stop treatment beforehand, you should discuss other options with your doctor.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The most common side effect in treatment with AGRASTAT is bleeding, which can occur anywhere in your body. This side effect can be serious and, rarely, can be fatal.

If you experience side effects, you may need medical attention. While you are using AGRASTAT, if you develop any of the following symptoms, you should contact your doctor immediately:

• Signs of intracranial bleeding such as headache, sensory deficits (visual or auditory), speech difficulties, numbness, or problems with movement or balance.
• Signs of internal bleeding such as coughing up blood or presence of blood in the urine or feces.
• Signs of serious allergic reactions such as difficulty breathing or dizziness.

The following side effects have occurred in patients treated with AGRASTAT. These side effects are listed in order of decreasing frequency.

Very common side effects (may affect more than 1 in 10 people):

Bleeding after surgery

Bleeding under the skin at the injection site, or in the muscle causing inflammation

Small red spots on the skin

Invisible blood in the urine or feces

Feeling dizzy

Headache

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

Blood in the urine

Coughing up blood

Nosebleeds

Bleeding in the gums and mouth

Bleeding at the puncture site

Decrease in blood count (decrease in hematocrit and hemoglobin)

Decrease in platelet count below 90,000/mm3

Fever

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

Bleeding in the stomach or intestine

Vomiting blood

Decrease in platelet count below 50,000/mm3

Side effects of unknown frequency (cannot be estimated from the available data):

Intracranial bleeding

Hematoma in the spinal region

Retroperitoneal bleeding

Accumulation of blood around the heart

Pulmonary bleeding

Acute and severe decrease in platelet count below 20,000/mm3

Severe allergic reactions with chest tightness, hives, including reactions that can cause difficulty breathing and dizziness.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.com. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of AGRASTAT

Your doctor or pharmacist knows how to store and dispose of this medicine.

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 bag after EXP. The expiry date is the last day of the month indicated.

Do not freeze.

Do not use AGRASTAT if there are visible particles or if the solution is discolored before use.

Medicines should not be disposed of via wastewater or household waste. Place the packaging and any unused medicine in the SIGRE collection point at the pharmacy. If in doubt, ask your pharmacist how to dispose of the packaging and any unused medicine. This will help protect the environment.

6. Container contents and additional information

Composition of AGRASTAT

The active ingredient is tirofiban hydrochloride monohydrate.

1 ml contains 281 micrograms of tirofiban hydrochloride monohydrate equivalent to 250 micrograms of tirofiban.

The other components are: sodium chloride, sodium citrate dihydrate, anhydrous citric acid, water for injection, hydrochloric acid and/or sodium hydroxide (for pH adjustment).

Appearance of AGRASTAT and container contents

AGRASTAT is a clear, colorless concentrated solution presented in 50 ml Type I glass vials.

Marketing authorization holder and manufacturer

Marketing authorization holder

Advanz Pharma Limited

Unit 17, Northwood House,

Northwood Crescent,

Dublin 9,

D09 V504,

Ireland

Manufacturer

Orion Corporation, Orion Pharma Espoo site

Orionintie 1, FI 00220, Espoo, Finland

ARVATO DISTRIBUTION GMBH, Gottlieb-Daimler-Strasse, 1 Harsewinkel, Germany 33428 Germany

Local representative:

Advanz Pharma Spain S.L.U.

Paseo de la Castellana 135,

7th floor, 28046 Madrid (Spain)

Phone: +34 900 834 889

[email protected]

Date of last revision of this prospectus:October 2013

Other sources of information

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/.

This information is intended only for healthcare professionals:

This product is intended only for hospital use, to be used by specialist physicians with experience in the treatment of acute coronary syndromes.

AGRASTAT concentrate must be diluted before use.

AGRASTAT must be administered with unfractionated heparin and oral antiplatelet treatment, including acetylsalicylic acid (ASA).

Posology and method of administration

In patients treated with an early invasive strategy for acute coronary syndrome without ST-segment elevation (NSTE-ACS) and who do not plan to undergo angiography for at least 4 hours and up to 48 hours after diagnosis, AGRASTAT is administered intravenously at an initial infusion rate of 0.4 micrograms/kg/min for 30 minutes. At the end of the initial infusion, AGRASTAT should be continued at a maintenance infusion rate of 0.1 micrograms/kg/min. AGRASTAT must be administered with unfractionated heparin (usually an intravenous bolus of 50-60 units/kg simultaneously with the start of AGRASTAT therapy, then approximately 1000 units/hour, adjusted according to the activated partial thromboplastin time (aPTT), which should be approximately twice the normal value) and oral antiplatelet treatment, including but not limited to ASA, unless contraindicated.

In patients with NSTE-ACS undergoing scheduled percutaneous coronary intervention (PCI) within the first 4 hours after diagnosis or in patients with acute myocardial infarction with scheduled primary PCI, AGRASTAT should be administered using an initial bolus of 25 micrograms/kg administered over a period of 3 minutes, followed by a continuous infusion at a rate of 0.15 micrograms/kg/min for 12-24 hours and up to 48 hours. AGRASTAT must be administered with unfractionated heparin (as described above) and oral antiplatelet treatment, including but not limited to acetylsalicylic acid (ASA), unless contraindicated.

No dose adjustment is required for elderly patients.

Patients with severe renal impairment

In severe renal impairment (creatinine clearance <30 ml min), the dose of agrastat should be reduced by 50%.< p>

Pediatric population

The safety and efficacy of AGRASTAT in children have not been established.

No data are available.

Initiation and duration of AGRASTAT

In patients treated with an early invasive strategy for acute coronary syndrome without ST-segment elevation (NSTE-ACS) and who do not plan to undergo angiography for at least 4 hours and up to 48 hours after diagnosis, the AGRASTAT dosing regimen should be started after diagnosis at a rate of 0.4 micrograms/kg/min. The recommended duration of maintenance infusion should be at least 48 hours. The infusion of AGRASTAT and unfractionated heparin should be maintained during coronary angiography and should be maintained for at least 12 hours and no more than 24 hours after angioplasty/atherectomy. Once the patient is clinically stable and no coronary intervention is planned by the physician, the infusion should be discontinued. The total duration of treatment should not exceed 108 hours.

If the patient with a diagnosis of NSTE-ACS is treated with an invasive strategy and undergoes angiography within 4 hours after diagnosis, the AGRASTAT bolus regimen of 25 micrograms/kg should be started at the beginning of PCI with a continuous infusion for 12 to 24 hours and up to 48 hours.

In patients with acute myocardial infarction with scheduled primary PCI, the bolus infusion regimen should be started as soon as possible after diagnosis.

Concomitant treatment (unfractionated heparin, oral antiplatelet treatment including ASA)

Treatment with unfractionated heparin is started with an intravenous bolus of 50-60 units/kg, and continued with a maintenance infusion of 1000 units per hour. The dose of heparin is titrated to maintain an activated partial thromboplastin time (aPTT) of approximately twice the normal value.

Unless contraindicated, all patients should receive oral antiplatelet agents, including but not limited to ASA, before starting treatment with AGRASTAT. This medication should be continued for at least the duration of the infusion with AGRASTAT.

Most studies investigating the administration of AGRASTAT as an adjunct to PCI have used ASA in combination with clopidogrel as oral antiplatelet treatment. The efficacy of the combination of AGRASTAT with prasugrel or ticagrelor has not been established in randomized, controlled trials.

If angioplasty (PCI) is required, heparin should be discontinued after PCI, and the cannulas should be removed once coagulation has returned to normal, for example, when the activated clotting time (ACT) is less than 180 seconds (usually 2-6 hours after discontinuing heparin).

Incompatibilities

There have been reports of incompatibility with diazepam. Therefore, AGRASTAT and diazepam should not be administered through the same intravenous line.

No incompatibilities have been found between AGRASTAT and the following intravenous formulations: atropine sulfate, dobutamine, dopamine, epinephrine hydrochloride, furosemide, heparin, lidocaine, midazolam hydrochloride, morphine sulfate, nitroglycerin, potassium chloride, propranolol hydrochloride, and injectable famotidine.

Instructions for use:

AGRASTAT Concentrate must be diluted before use:

1. Withdraw 50 ml from a 250 ml container of 0.9% sterile saline solution or 5% glucose solution in water and replace it with 50 ml of AGRASTAT (from a 50 ml vial) to achieve a concentration of 50 micrograms/ml. Mix well before use.

1. Use according to the dosing table.

The following table is provided as a guide for dose adjustment based on weight.

AGRASTAT Concentrate must be diluted first as indicated inInstructions for use

• Whenever the solution and container permit, parenteral drugs should be inspected for visible particles or coloration before use.
• AGRASTAT should only be administered intravenously and can be administered with unfractionated heparin through the same infusion line.
• It is recommended to administer AGRASTAT with a calibrated infusion device using sterile material.
• Care should be taken not to prolong the infusion of the initial dose and to avoid calculation errors of the infusion rates for the maintenance dose based on the patient's weight.

Special precautions for storage

Do not use AGRASTAT after the expiration date stated on the label and outer packaging. The expiration date is the last day of the month indicated.

Do not freeze. Keep the container in the carton to protect it from light.

After dilution, the product must be used immediately. If not used immediately, the storage conditions should not exceed 24 hours at 2 - 8°C.

Appearance of the product and container contents

AGRASTAT is a clear, colorless concentrated solution presented in 50 ml Type I glass vials.

Special precautions for disposal and other handling

Disposal of unused medicinal products and all materials that have come into contact with them should be carried out in accordance with local regulations.

“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/”