Antithrombin III Baxalta

Package leaflet: Information for the patient

ANTITHROMBIN III BAXALTA powder and solvent for solution for infusion

Human plasma-derived Antithrombin III
Please read this leaflet carefully before 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 experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

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

1. What ANTITROMBINA III BAXALTA is and what it is used for

ANTITROMBINA III BAXALTA is a medicine containing human plasma-derived antithrombin III.
Antithrombin has an anticoagulant effect, meaning it makes the blood less likely to clot.
If you suffer from congenital or acquired antithrombin deficiency, your antithrombin levels are lower than normal, and you may have an increased tendency to form blood clots in blood vessels, or a reduced or absent response to heparin.
ANTITROMBINA III BAXALTA is used in adults and children aged 6 years and older
for the prevention and treatment of blood clot formation due to:

1. Congenital antithrombin deficiency, particularly in connection with surgery, pregnancy or childbirth.
2. Acquired antithrombin deficiency, particularly in cases of:
   • Risk or obstruction of blood vessels in patients with kidney or liver disease (nephrotic syndrome or enteropathies).
   • Surgical procedures and massive bleeding in patients with severe liver disease, especially when this requires replacement therapy with coagulation factor concentrates (prothrombin complex).

2. What you need to know before using ANTITHROMBIN III BAXALTA

Do not use ANTITHROMBIN III BAXALTA

• if you are allergic to antithrombin III derived from human plasma or to any of the other ingredients of this medicine (listed in section 6),
• if you have previously had heparin-induced thrombocytopenia (a decrease in platelet count), another medicine used to make the blood less prone to clotting.

Warnings and precautions
Traceability
To improve the traceability of biological medicines, the name and batch number of the administered medicine must be clearly recorded.
Talk to your doctor before using ANTITHROMBIN III BAXALTA.
Your doctor will carry out checks and tests during treatment with ANTITHROMBIN III BAXALTA.
Transmissible agents
ANTITHROMBIN III BAXALTA is a medicine derived from human blood or plasma (the liquid component of blood). When medicines are produced from human blood or plasma, certain safety measures are applied to prevent transmission of infections to patients. These include:

• careful selection of blood and plasma donors to ensure that potential carriers of infection are excluded,
• testing of each individual donation and plasma pool to detect signs of the presence of viruses and infections,
• inclusion of steps during the processing of blood or plasma that can inactivate or remove viruses. Despite these measures, whenever medicines prepared from human blood or plasma are administered, the possibility of transmitting an infection cannot be completely ruled out. This also applies to unknown or emerging viruses or other types of infections.

The measures taken are considered effective against lipid-enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), as well as against non-lipid-enveloped viruses such as hepatitis A virus (HAV) and parvovirus B19.
Your doctor may recommend appropriate vaccination against hepatitis A and B if you receive regular or repeated treatment with medicines derived from human plasma.

Children
There are no data available to support the use of ANTITHROMBIN III BAXALTA in children under 6 years of age.

Other medicines and ANTITHROMBIN III BAXALTA
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
In particular, inform your doctor if you are taking heparin, a medicine used to make the blood less prone to clotting, as this increases the risk of bleeding, especially if you have a reduced number of platelets (thrombocytopenia). The effect of antithrombin is strongly enhanced by heparin. Your doctor may ask you to have regular blood tests to monitor blood fluidity.

Pregnancy, breast-feeding and fertility
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breast-feeding, consult your doctor before using this medicine.
Experience regarding the safety of antithrombin-containing products administered during pregnancy or breast-feeding has not been evaluated in controlled clinical studies and is therefore limited.
Your doctor will administer ANTITHROMBIN III BAXALTA during pregnancy and the breast-feeding period only if clearly necessary, taking into account that during pregnancy there is an increased risk of thromboembolic events.

Driving and using machines
No effects on the ability to drive and use machines have been observed.

ANTITHROMBIN III BAXALTA contains sodium
500 UI/10 ml:
This medicine contains 37.7 mg of sodium (the main component of table salt) per vial. This corresponds to 1.9% of the maximum daily dietary intake recommended for an adult.
1000 UI/20 ml:
This medicine contains 75.5 mg of sodium (the main component of table salt) per vial. This corresponds to 3.8% of the maximum daily dietary intake recommended for an adult.

3. How to use ANTITROMBINA III BAXALTA

Use this medicine exactly as instructed by your doctor or pharmacist. If you have
any doubts, consult your doctor or pharmacist.
This medicine must be administered into a vein, always following your doctor's instructions exactly.
Your doctor will determine the dose based on your family history and your health status.
If you use more ANTITROMBINA III BAXALTA than you should
To date, symptoms of overdose with antithrombin have not been reported.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
If you experience any of the following side effects during treatment with ANTITHROMBIN III BAXALTA,
inform your doctor or nurse immediately, who will IMMEDIATELY STOP the
administration at the first sign of trouble and will provide appropriate treatment for these
symptoms, which may be life-threatening, such as:
hypersensitivity and allergic reactions, which in some cases may progress to severe allergic reactions (anaphylaxis) affecting the entire body.
Allergic reactions may include the following symptoms:
o facial swelling (angioedema), hives, chest tightness, difficulty breathing (dyspnea), low blood pressure;
o reduced blood flow to organs (shock);
o burning and irritation at the injection site, chills, redness,
o headache, drowsiness, nausea, restlessness, rapid heartbeat (tachycardia),
fever, tingling, vomiting.
Immediate availability of appropriate equipment, medications, and healthcare personnel for emergency treatment of these side effects is essential.
Side effects observed with unknown frequency (frequency cannot be estimated from the available data):

• hypersensitivity, anaphylactic reaction
• tremor
• hot flushes

Blood-related side effects
Rarely, a reduction in the number of blood platelets (heparin-induced immune-mediated thrombocytopenia) may occur. In these cases, platelet counts may decrease by 50% or fall below 100,000/microlitre.
Fever has been observed on rare occasions.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via
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 ANTITROMBINA III BAXALTA

Store in a refrigerator (2 °C–8 °C).
Do not freeze.
Keep in the original packaging to protect the medicine from light.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton after “Exp.:”.
The expiry date refers to the last day of that month.
Do not use this medicine if you notice solutions that are not clear or contain deposits.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What ANTITROMBINA III BAXALTA contains

• The active substance is antithrombin III derived from human plasma.
• The other excipients are glucose, sodium chloride, sodium citrate dihydrate (see section 2 “ANTITROMBINA III BAXALTA contains sodium”), tris(hydroxymethyl)aminomethane, water for injections (solvent). ANTITROMBINA III BAXALTA is supplied as a powder and solvent for infusion solution containing:

This medicinal product contains 0.164 mmol (3.77 mg) of sodium per ml.
Description of the appearance of ANTITHROMBIN III BAXALTA and contents of the pack
ANTITHROMBIN III BAXALTA is a powder or brittle solid with a colour ranging from light yellow to light green. The solvent (water for injections) is a clear, colourless liquid.
After reconstitution, the solution is yellow, clear or slightly opalescent.
ANTITHROMBIN III BAXALTA powder and solvent are contained in vials closed with rubber stoppers and protective caps.
ANTITHROMBIN III BAXALTA is available in the following pack sizes:

• one vial of 500 IU powder, one vial of 10 ml solvent, and a set for reconstitution and injection
• one vial of 1000 IU powder, one vial of 20 ml solvent, and a set for reconstitution and injection

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Baxalta Innovations GmbH
Industriestrasse 67, A - 1221 Vienna, Austria
Local representative in Italy:
Takeda Italia S.p.A.
Tel. +39 06 502601
Manufacturer
Baxter AG, Industriestrasse 67, A - 1221 Vienna, Austria
Takeda Manufacturing Austria AG, Industriestrasse 67, A-1221 Vienna, Austria

The following information is intended exclusively for physicians or healthcare professionals:
Interactions with other medicinal products
Heparin: replacement therapy with antithrombin during administration of heparin at therapeutic doses increases the risk of bleeding. The effect of antithrombin is strongly potentiated by heparin. The half-life of antithrombin may be considerably reduced by concomitant treatment with heparin due to an accelerated turnover of antithrombin. Therefore, the simultaneous administration of heparin and antithrombin in a patient with an increased risk of bleeding must be clinically and biologically monitored.
In general, for combination therapy with heparin, regular monitoring of the PTT (partial thromboplastin time) is recommended, with corresponding adjustment of the heparin dosage.
Furthermore, in patients with thrombocytopenia, there may be a deficiency of platelet factor 4, which contributes to reduced neutralisation of heparin, thereby increasing the bleeding tendency.
Special warnings and precautions for use
As with any intravenous protein product, allergic-type hypersensitivity reactions may occur. Patients must be closely monitored and carefully observed for any symptoms during the infusion period. Patients should be informed about the early signs of hypersensitivity reactions, including urticaria, even generalized, chest tightness, dyspnoea, hypotension, and anaphylaxis. If such symptoms occur, patients should contact their physician immediately.
In case of shock, standard medical procedures for the treatment of shock should be followed.
In the event of allergic or anaphylactic reactions, administration must be stopped immediately.
Mild reactions may be managed with antihistamines. Treatment of severe hypotensive reactions follows modern shock management protocols.
Appropriate vaccination (hepatitis A and B) should be considered for patients receiving regular human antithrombin.
Traceability
In order to improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.
Clinical and biological monitoring when antithrombin is used concomitantly with heparin:

• to adjust the heparin dosage and to avoid excessive hypocoagulability, regular monitoring of the degree of anticoagulation (APTT and, where appropriate, anti-FXa activity) should be performed at close intervals, particularly during the first minutes/hours following the initiation of antithrombin administration;
• to adjust the individual dosage, antithrombin levels should be monitored daily due to the risk of decreased antithrombin levels associated with prolonged treatment with unfractionated heparin.

Dosage and method of administration
Treatment must be initiated under the supervision of a physician experienced in managing patients with antithrombin deficiency.
Dosage
In congenital deficiencies, dosage must be individualised for each patient, taking into account family history, particularly with regard to thromboembolic events, existing clinical risk factors, and laboratory assessments.
The dosage and duration of replacement therapy in acquired deficiencies depend on the plasma antithrombin level, the presence of signs of increased turnover, the underlying disease, and the severity of the clinical condition. The amount to be administered and the frequency of administration must always be based, on a case-by-case basis, on clinical efficacy and laboratory assessments.
The quantity of antithrombin units administered is expressed in International Units (IU), which are related to the current WHO standard for antithrombin. Antithrombin activity in plasma is expressed both as a percentage (relative to normal human plasma) and as International Units (relative to the international standard for plasma antithrombin).

1. Specific dosage recommendations for consumption coagulopathy

An essential prerequisite for adequate dosing is the determination of antithrombin III activity, to be performed before starting therapy and subsequently at short intervals of approximately 4–6 hours. Plasma levels should be increased to at least 80–100% of normal values. If activity drops below 70%, additional administration is required. For calculating the dose, the following indicative formula may be applied:
IU of AT III to be infused = ID x body weight in kg
ID = Desired Increase in Antithrombin III (difference between the target AT III activity level and the baseline value).

When heparin is administered concomitantly, it must be borne in mind that its effect is potentiated by antithrombin III (see section "Interactions with other medicinal products").

2. Specific dosage indications for other antithrombin III deficiency states

A typical initial dose is approximately 1500 IU, followed by half the initial dose at intervals of 8–24 hours.
To determine the exact dose, measurement of antithrombin III activity is essential.
The following indicative formula may be used for dose calculation:
IU of AT III to be infused = ID × body weight in kg