Agrastat 0.05 mg/ml solution for infusion

Patient Information Leaflet

Introduction

Package leaflet: Information for the patient

AGRASTAT 0.05 mg/ml solution for infusion

(tirofiban)

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 or pharmacist.
• This medicine has been prescribed for you only, and you should not give it to other people, even if they have the same symptoms as you. It may harm them.
• If you experience any side effects, talk to your doctor or pharmacist, even if they are side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

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

1. What AGRASTAT is and what it is used for

AGRASTAT is used to help improve blood flow to the heart and to prevent chest pain and heart attacks. It works by preventing platelets, which are blood cells, from clumping together and forming blood clots.

This medicine may also be used in patients whose arteries are widened with a balloon (percutaneous coronary intervention or PCI). This is a procedure achieved by implanting a small tube (stent) to improve blood flow to the heart.

AGRASTAT is intended to be used with aspirin and unfractionated heparin.

2. What you need to know before using AGRASTAT

Do not use AGRASTAT:

• If you are allergic (hypersensitive) to tirofiban or to any of the other components of AGRASTAT (listed in section 6).
• If you have internal bleeding or a history of internal bleeding within 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 in the same therapeutic group.
• If you have had a stroke within the previous 30 days or any history of hemorrhagic stroke.
• If you have had major trauma or major surgery within the past six weeks.
• If you have severe liver failure.

Your doctor will review your medical history to determine if you are at increased risk of side effects associated with the use of this medicine.

Warnings and precautions

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

• Any medical condition.
• Any allergies.
• Cardiopulmonary resuscitation, biopsy, or lithotripsy within the last 2 weeks.
• Major trauma or major surgery within the last 3 months.
• A stomach or intestinal (duodenal) ulcer within the last 3 months.
• Recent bleeding disorder (within the last year), such as gastrointestinal bleeding, blood in urine or stools.
• Recent spinal procedure.
• History or symptoms of aortic rupture (aortic dissection).
• Uncontrolled high blood pressure.
• Inflammation of the membrane lining the heart (pericarditis).
• Inflammation of blood vessels (active vasculitis).
• Hemorrhagic retinopathy.
• Thrombolytic treatment.
• Liver disease.
• Insertion of a special intravenous catheter below the clavicle within the last 24 hours.
• Heart failure.
• Low blood pressure due to heart failure (cardiogenic shock).
• Liver disorder.
• Low blood count or anemia.

Use of AGRASTAT with other medicines

In general, AGRASTAT can be used with other medicines. Please tell your doctor if you are taking, have recently taken, or might take any other medicines, including over-the-counter medicines, as they may affect the action of these medicines. It is very important that you inform your doctor if you are taking medicines that prevent blood clotting, such as warfarin.

Use of 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 plan to become pregnant, consult your doctor before using this medicine.

Driving and use of 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 917 mg of sodium per 250 ml bag. This should be taken into consideration in patients on a sodium-controlled diet.

3. How to use AGRASTAT

AGRASTAT must be prescribed by qualified physicians experienced in the management of acute coronary syndromes.

AGRASTAT is administered intravenously. Your doctor will determine the appropriate dose based on your condition and body weight.

Use in children

Use in children is not recommended.

If you use more AGRASTAT than you should

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

The most commonly reported adverse effect of overdose is bleeding. If you experience bleeding, you must inform your doctor immediately.

In case of overdose or accidental ingestion, contact your doctor or pharmacist immediately or call the Toxicology Information Service at telephone number: 91 562 04 20, indicating the medication and the amount ingested.

If you forget to use AGRASTAT

Your doctor will decide when AGRASTAT should be administered.

If you stop using AGRASTAT

Your doctor will decide when treatment should be discontinued. However, if you wish to stop treatment earlier, you should discuss alternative options with your doctor.

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

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

The most common adverse effect during treatment with AGRASTAT is bleeding, which may occur anywhere in the body. This adverse effect can be serious and, rarely, may be fatal.

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

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

The following is a list of adverse effects reported in patients treated with AGRASTAT. These adverse effects are listed in decreasing order of frequency.

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

• Bleeding after surgery
• Bleeding under the skin at the injection site or into muscle, causing swelling
• Small red spots on the skin (petechiae)
• Blood not visible to the naked eye in urine or stools
• Dizziness
• Headache

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

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

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

• Bleeding in stomach or intestine
• Vomiting blood
• Decrease in platelet count below 50,000/mm³

Adverse effects with unknown frequency (cannot be estimated from available data):

• Intracranial bleeding
• Spinal hematoma
• Retroperitoneal bleeding
• Accumulation of blood around the heart (cardiac tamponade)
• Pulmonary hemorrhage
• Acute and severe decrease in platelet count below 20,000/mm³
• Severe allergic reactions with chest tightness, hives, including reactions that may cause difficulty breathing and dizziness.

Reporting of adverse effects

If you experience any type of adverse effect, talk to your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicinal Products: www.notificaRAM.com.

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

5. Storage of AGRASTAT

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

Keep out of the sight and reach of children.

Do not use this medicine after the expiry date stated on the bag after EXP. The expiry date is the last day of the month indicated.

Do not freeze.

Keep the container in the outer laminated bag to protect it from light.

Do not use this medicine if visible particles are present or if the solution is discolored before use.

Medicines should not be disposed of via wastewater or household waste. Dispose of unused containers and medicines at the SIGRE collection point at your pharmacy. If you are in doubt, ask your pharmacist how to dispose of containers and medicines you no longer need. This will help protect the environment.

6. Contents of the pack and other information

Composition of AGRASTAT

The active substance is tirofiban hydrochloride monohydrate.

1 ml of AGRASTAT infusion solution contains 56 micrograms of tirofiban hydrochloride monohydrate, equivalent to 50 micrograms of tirofiban.

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

Appearance of AGRASTAT and pack contents

AGRASTAT is a clear, colourless solution available as:

Freeflex® 250 ml pack (non-PVC plastic), colourless, multilayer polyolefin film bag with injection-moulded polyolefin tubing, further packaged in a pre-printed aluminium foil pouch.

Pack size: 1 or 3 packs containing 250 ml of infusion solution. Some pack sizes may not be marketed.

Marketing Authorisation Holder and Manufacturer:

Marketing Authorisation Holder

Advanz Pharma Limited

Unit 17, Northwood House,

Northwood Crescent,

Dublin 9,

D09 V504,

Ireland

Manufacturer

ARVATO DISTRIBUTION GMBH

Gottlieb-Daimler-Strasse, 1

33428 Harsewinkel, Germany

Tjoapack Netherlands B.V.

Nieuwe Donk 9,

Etten-Leur, 4879 AC,

The Netherlands

Local representative:

Advanz Pharma Spain S.L.U.

Paseo de la Castellana 135, 7th floor

28046 Madrid (Spain)

Tel: +34 900 834 889

[email protected]

Date of latest revision of this package leaflet: August 2024

Other sources of information

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

This information is intended for healthcare professionals only:

This product is intended exclusively for hospital use and must be administered by physicians experienced in the treatment of acute coronary syndromes.

Agrastat must be administered with unfractionated heparin and oral antiplatelet therapy, 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) who are not scheduled to undergo angiography within 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 should be administered with unfractionated heparin (typically an intravenous bolus of 50–60 units (U)/kg given simultaneously with the initiation of AGRASTAT therapy, followed by approximately 1,000 (U) per hour, adjusted according to activated partial thromboplastin time (aPTT), which should be approximately twice the normal value) and oral antiplatelet therapy, including but not limited to ASA, unless contraindicated.

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

No dose adjustment is required for elderly patients.

Patients with severe renal impairment

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

Paediatric 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) who are not scheduled to undergo angiography within at least 4 hours and up to 48 hours after diagnosis, the AGRASTAT dosing regimen should be initiated after diagnosis at 0.4 micrograms/kg/min as a loading dose. The recommended duration of maintenance infusion should be at least 48 hours. Infusion of AGRASTAT and unfractionated heparin should continue 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 further coronary intervention is planned by the physician, the infusion should be discontinued. Total duration of treatment should not exceed 108 hours.

If a patient diagnosed with NSTE-ACS is treated with an invasive strategy and undergoes angiography within 4 hours after diagnosis, the bolus dosing regimen of AGRASTAT (25 micrograms/kg) should be initiated at the beginning of PCI, followed by continuous infusion for 12 to 24 hours and up to 48 hours. In patients with acute myocardial infarction undergoing scheduled primary PCI, the bolus infusion regimen should be initiated as soon as possible after diagnosis.

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

Unfractionated heparin therapy is initiated with an intravenous bolus of 50–60 U/kg and continued with a maintenance infusion of 1,000 units per hour. Heparin dosage should be 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, prior to initiation of AGRASTAT therapy. This medication should be continued for at least the duration of AGRASTAT infusion.

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

If angioplasty (PCI) is required, heparin should be discontinued after PCI, and catheters should be removed once coagulation has returned to normal, e.g., when activated clotting time (ACT) is less than 180 seconds (typically 2–6 hours after discontinuation of heparin).

Incompatibilities

Incompatibility has been reported with diazepam. Therefore, AGRASTAT and diazepam must 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:

Check the expiry date.

Do not withdraw solution directly from the container with a syringe.

To open: tear the overwrap at the notch and remove the inner container (250 ml of infusion solution). Check for microleaks by firmly compressing the inner bag. If leakage is observed, discard the solution, as sterility may be compromised.

Do not use unless the solution is clear and the closure is intact.

Do not add supplementary medication or withdraw solution directly from the bag with a syringe.

PRECAUTION: Do not use plastic containers in series connections, as this may result in air embolism due to residual air being drawn from the primary container before completion of fluid administration from the secondary container.

Preparation for administration

	Identify the blue infusion port
	Remove the blue protective cap from the Freeflex® infusion port. The inner membrane acts as a sterile cover: disinfection of the membrane is not required!
	Close the roller clamp. Insert the spike until the blue plastic collar of the port meets the shoulder of the spike. Use a non-vented set or close the air inlet.
	Hang the bag on the infusion stand. Squeeze the drip chamber to achieve proper fluid level. Prime the infusion set. Connect and adjust the flow. Use according to the dosage table.

The following table is provided as a guide for dose adjustment according to body weight.

	0.4 micrograms/kg/min Loading Dose Regimen Most Patients	0.4 micrograms/kg/min Loading Dose Regimen Severe Renal Impairment	25 micrograms/kg Bolus Dose Regimen Most Patients	25 micrograms/kg Bolus Dose Regimen Severe Renal Impairment
Patient Weight (kg)	Loading Infusion Rate 30 min (ml/h)	Maintenance Infusion Rate (ml/h)	Loading Infusion Rate 30 min (ml/h)	Maintenance Infusion Rate (ml/h)	Bolus (ml)	Maintenance Infusion Rate (ml/h)	Bolus (ml)	Maintenance Infusion Rate (ml/h)
30–37	16	4	8	2	17	6	8	3
38–45	20	5	10	3	21	7	10	4
46–54	24	6	12	3	25	9	13	5
55–62	28	7	14	4	29	11	15	5
63–70	32	8	16	4	33	12	17	6
71–79	36	9	18	5	38	14	19	7
80–87	40	10	20	5	42	15	21	8
88–95	44	11	22	6	46	16	23	8
96–104	48	12	24	6	50	18	25	9
105–112	52	13	26	7	54	20	27	10
113–120	56	14	28	7	58	21	29	10
121–128	60	15	30	8	62	22	31	11
129–137	64	16	32	8	67	24	33	12
138–145	68	17	34	9	71	25	35	13
146–153	72	18	36	9	75	27	37	13

• Whenever solution and container permit, parenteral medicinal products should be inspected visually for particulate matter or discoloration prior to administration.
• AGRASTAT must be administered only intravenously and may be co-administered with unfractionated heparin through the same infusion line.
• It is recommended to administer AGRASTAT using a calibrated infusion set with sterile equipment.
• Care must be taken not to prolong the infusion of the initial dose and to avoid calculation errors in infusion rates for the maintenance dose based on the patient's body weight.

Special storage precautions

Do not use AGRASTAT after the expiry date stated on the bag. The expiry date refers to the last day of the month indicated.

Do not freeze. Keep the container in the outer laminated bag (250 ml infusion solution) to protect it from light.

Appearance of the product and contents of the container

AGRASTAT is a clear, colourless solution available as:

Freeflex® container – 250 ml (non-PVC plastic), colourless, with multiple polyolefin layers and polyolefin injection-moulded tubing. Packaged in a pre-printed outer laminated bag.

Pack sizes: 1 or 3 containers with 250 ml of infusion solution. Some pack sizes may not be marketed.

Special precautions for disposal and other handling

Disposal of unused medicine and of all materials that have come into contact with it must be carried out in accordance with local regulations.

"Detailed and up-to-date 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/"