Aggrastat

Package leaflet: Information for the user

Aggrastat 250 micrograms/ml

concentrate for solution for infusion
tirofiban
Please read all of this leaflet carefully before you start using this medicine, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Aggrastat is and what it is used for

Aggrastat is used to help improve blood flow to the heart and to help prevent chest pain and heart attacks. It works by preventing platelets (blood cells) from clumping together and forming clots.
This medicine may also be used in patients undergoing coronary angioplasty, a procedure in which the heart's blood vessels are widened using a balloon, sometimes combined with the placement of a small tube (stent), to improve blood flow to the heart.
Aggrastat must be used in combination with aspirin and unfractionated heparin.

2. What you need to know before using Aggrastat

Do not use Aggrastat

• if you are allergic (hypersensitive) to tirofiban or to any of the other ingredients of Aggrastat (listed in section 6 “What Aggrastat contains”)
• if you have internal bleeding or have had internal bleeding within the last 30 days
• if you have a history of cerebral haemorrhage, brain tumour, or abnormalities in the blood vessels of the brain
• if you suffer from uncontrolled severe hypertension (malignant hypertension)
• if you have low platelet count (thrombocytopenia) or blood clotting disorders
• if you developed thrombocytopenia after previous treatment with Aggrastat or another medicine in the same class
• if you have had a stroke within the last 30 days or a previous stroke with haemorrhage
• if you have sustained severe trauma or undergone major surgery within the last 6 weeks
• if you have severe liver disease.

Your doctor will evaluate your medical history to determine whether you are at increased risk of adverse effects associated with the use of this medicine.
Warnings and precautions
Talk to your doctor before using Aggrastat if you have had or currently have:

• any medical condition
• any allergies
• cardiopulmonary resuscitation (CPR), a biopsy, or a procedure to crush kidney stones within the last 2 weeks
• severe trauma or major surgery within the last 3 months
• a stomach or intestinal (duodenal) ulcer within the last 3 months
• a recent bleeding disorder (within the last year), such as gastrointestinal bleeding or blood in urine or stools
• a recent spinal procedure
• history or symptoms of aortic rupture (aortic dissection)
• uncontrolled hypertension
• inflammation of the lining surrounding the heart (pericarditis)
• inflammation of blood vessels (vasculitis)
• blood vessel problems in the back of the eye (retina)
• treatment with medicines that help prevent or dissolve blood clots
• kidney problems
• an intravenous catheter inserted under the clavicle within the last 24 hours
• heart failure
• very low blood pressure due to heart failure (cardiogenic shock)
• liver disease
• low blood cell count or anaemia.

Other medicines and Aggrastat
In general, Aggrastat can be used with other medicines. Inform your doctor if you are taking, have recently taken, or might take any other medicines, including those without a prescription, as some of them may affect the action of other medicines. It is particularly important that you inform your doctor if you are taking other medicines that prevent blood clot formation, such as warfarin.
Aggrastat with food and drink
Food and drink have no effect on this medicine.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor before using this medicine.
Driving and using machines
Due to your medical condition, you will not be able to drive or operate machinery while receiving Aggrastat.
Aggrastat contains sodium
This medicine contains approximately 189 mg of sodium per 50 ml vial; this should be taken into consideration in patients following a controlled sodium diet.

3. How to use Aggrastat

Aggrastat must be prescribed by a qualified doctor experienced in the treatment of heart attacks.
Aggrastat will be, or has been, administered to you intravenously. The doctor will determine the appropriate dose, which will depend on your condition and body weight.

Use in children
Use in children is not recommended.

If you use more Aggrastat than you should
Your Aggrastat dose will be carefully monitored and controlled by the doctor and pharmacist.
The most common symptom of an overdose is bleeding. If you experience bleeding, inform healthcare professionals immediately.

If you forget to use Aggrastat
The doctor will decide when to administer the dose.

If you stop using Aggrastat
The doctor will decide when treatment should end. However, if you wish to discontinue therapy earlier, discuss alternative options with your doctor.

If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

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

The most common side effect of Aggrastat is bleeding, which can occur anywhere in the body. This may become severe and, rarely, fatal.
If you experience any side effects, they may require medical intervention. During treatment with Aggrastat, contact your doctor immediately if you develop any of the following symptoms:

• signs of intracranial bleeding such as headache, sensory disturbances (visual or auditory), difficulty speaking, numbness, or movement or balance problems
• signs of internal bleeding, such as coughing up blood or blood in the urine or stools
• signs of severe allergic reactions, such as difficulty breathing and dizziness.

Below is a list of side effects reported in some individuals treated with Aggrastat. Side effects are listed in decreasing order of frequency.

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

• Bleeding following surgical procedures
• Bleeding under the skin at the site of an injection or into a muscle, causing swelling
• Small red spots on the skin (petechiae)
• Blood in urine or stools not visible to the naked eye (occult blood)
• Nausea
• Headache

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

• Blood in urine
• Coughing up blood
• Nosebleeds
• Bleeding from gums or mouth
• Bleeding from the site of vascular puncture
• Reduction in red blood cells (decreased hematocrit and hemoglobin)
• Reduction in platelet count below 90,000/mm³
• Fever

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

• Bleeding in the stomach or intestines
• Vomiting blood
• Reduction in platelet count below 50,000/mm³

Not known (frequency cannot be estimated from the available data):

• Bleeding within the skull (intracranial hemorrhage)
• Hematoma in the spinal region
• Bleeding in internal abdominal organs
• Accumulation of blood around the heart (cardiac tamponade)
• Bleeding in the lungs
• Acute and/or severe reduction in platelet count below 20,000/mm³
• Severe allergic reactions with chest tightness, hives, including reactions causing difficulty breathing and dizziness

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please inform your doctor or pharmacist. You can also report side effects directly via the national reporting system at http://www.agenziafarmaco.gov.it/it/responsabili.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Aggrastat

Your doctor and pharmacist know 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 label and on the outer packaging after 'Exp.'. The expiry date refers to the last day of that month.
Do not freeze. Keep the container in the outer packaging to protect the medicine from light.
Do not use this medicine if you notice visible particles or discoloration of the solution before use.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Aggrastat contains
The active substance is tirofiban hydrochloride monohydrate.
1 ml of Aggrastat contains 281 micrograms of tirofiban hydrochloride monohydrate (equivalent to 250 micrograms of tirofiban).
The other components are sodium chloride, disodium citrate dihydrate, anhydrous citric acid, water for injectable preparations, hydrochloric acid and/or sodium hydroxide (for pH adjustment).

Description of the appearance of Aggrastat and contents of the pack
Aggrastat is a clear, colourless concentrated solution available in a 50 ml Type I glass vial.

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
02200 Espoo
Finland

Other sources of information
More detailed information on this medicinal product is available on the website of the Italian Medicines Agency: http://www.agenziafarmaco.gov.it

The following information is intended exclusively for healthcare professionals:

This product is for hospital use only, administered by specialist physicians experienced in the management of acute coronary syndromes.
Aggrastat concentrate must be diluted before use.
Aggrastat concentrate must be administered in combination with unfractionated heparin and oral antiplatelet agents, including acetylsalicylic acid (ASA).

Dosage and method of administration

In patients treated with an early invasive strategy for acute coronary syndromes without ST-segment elevation (NSTE-ACS), but for whom angiography is not scheduled within at least 4 hours and up to 48 hours after diagnosis, Aggrastat is administered intravenously at an initial infusion rate of 0.4 micrograms/kg/min for 30 minutes. At the end of this initial infusion, Aggrastat should be continued at a maintenance infusion rate of 0.1 micrograms/kg/min. Aggrastat must be administered together with unfractionated heparin (usually an intravenous bolus of 50–60 units [U]/kg given at the start of Aggrastat therapy, followed by approximately 1,000 U per hour, adjusted based on activated partial thromboplastin time [aPTT], which should be about twice the normal value) and oral antiplatelet therapy, including but not limited to ASA, unless contraindicated.

In patients with NSTE-ACS scheduled for percutaneous coronary intervention (PCI) within 4 hours of diagnosis, or in patients with acute myocardial infarction scheduled for primary PCI, Aggrastat should be administered using an initial bolus of 25 micrograms/kg given over 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. Aggrastat must be administered with unfractionated heparin (dosing as described above) and oral antiplatelet therapy, including but not limited to ASA, unless contraindicated.

Dose adjustment is not required in elderly patients.

Patients with severe renal impairment
In severe renal impairment (creatinine clearance <30 ml/min), the dose of Aggrastat should be reduced by 50%.

Paediatric population
The safety and efficacy of Aggrastat in children has not been established.
No data are available.

Initiation and duration of Aggrastat therapy
In patients treated with an early invasive strategy for NSTE-ACS, but for whom angiography is not scheduled within at least 4 hours and up to 48 hours after diagnosis, the loading dose of Aggrastat at 0.4 micrograms/kg/min should be initiated immediately after diagnosis. The recommended duration of the maintenance infusion should be at least 48 hours. The infusion of Aggrastat and unfractionated heparin may continue during coronary angiography and must be maintained for at least 12 hours and no longer than 24 hours after angioplasty/atherectomy. The infusion should be discontinued once the patient is clinically stable and no further coronary interventions are planned by the treating physician. Total treatment duration must not exceed 108 hours.

If a patient diagnosed with NSTE-ACS undergoes an invasive procedure and undergoes angiography within 4 hours of diagnosis, the bolus regimen of Aggrastat at 25 micrograms/kg should be initiated at the beginning of coronary angioplasty, with the infusion continued for 12–24 hours and up to 48 hours. In patients with acute myocardial infarction undergoing primary PCI, the bolus should be administered as soon as possible after diagnosis.

Concomitant therapy (unfractionated heparin, oral antiplatelet therapy, including ASA)
Unfractionated heparin therapy should be initiated with an intravenous bolus of 50–60 U/kg, followed by a maintenance infusion of 1,000 U per hour. The heparin dose should be titrated to maintain an aPTT of approximately twice the normal value.

Unless contraindicated, all patients should receive oral antiplatelet agents, including but not limited to ASA, prior to initiation of Aggrastat therapy. This treatment should continue for at least the entire duration of Aggrastat infusion.

Most studies evaluating Aggrastat administration as adjunct to PCI used ASA in combination with clopidogrel as oral antiplatelet therapy.
The efficacy of combining Aggrastat with prasugrel or ticagrelor has not been established in randomized controlled clinical trials.

If percutaneous coronary intervention (PCI) is required, heparin should be discontinued at the end of the procedure, and the introducer sheath should be removed once coagulation has returned to normal, e.g., when activated clotting time (ACT) is less than 180 seconds (usually 2–6 hours after heparin discontinuation).

Incompatibilities
Incompatibility has been observed with diazepam. Therefore, Aggrastat and diazepam must not be administered through the same intravenous line.

No incompatibilities have been observed between Aggrastat and the following intravenous medications: atropine sulfate, dobutamine, dopamine, epinephrine HCl, furosemide, heparin, lidocaine, midazolam HCl, morphine sulfate, nitroglycerin, potassium chloride, propranolol HCl, and injectable famotidine.

Instructions for use

Aggrastat concentrate must be diluted before use:

1. Remove 50 mL from a container with 250 mL of sterile 0.9% sodium chloride solution or 5% dextrose solution and replace with 50 mL of Aggrastat (from a 50 mL unit-dose vial) to achieve a concentration of 50 micrograms/mL. Mix well before use.
2. Use according to the doses reported in the following table:

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

Aggrastat concentrate must first be diluted as indicated in the Instructions for Use.

• Where possible, parenteral medicines should be inspected visually for particulate matter or discoloration prior to administration.
• Aggrastat must be administered only intravenously and may be administered with unfractionated heparin through the same infusion line.
• It is recommended that Aggrastat be administered using a calibrated infusion set with sterile equipment.
• Care should be taken to ensure that the infusion time of the loading dose is not prolonged and that calculation errors in the infusion rate based on patient weight for the maintenance dose are avoided.

Special precautions for storage
Do not use Aggrastat after the expiry date stated on the label and outer packaging following "Exp." The expiry date refers to the last day of that month.
Do not freeze. Keep the container in the outer packaging to protect the medicine from light.
After dilution, the product should be used immediately. If not used immediately, storage conditions should normally not exceed 24 hours at 2–8°C.

Nature and contents of container
Aggrastat is a clear, colourless concentrated solution available in a 50 ml Type I glass vial.

Special precautions for disposal and handling
Unused medicine and waste material arising from this medicine must be disposed of in accordance with local regulations.