Consumer medicine information

Thrombotrol-VF

Antithrombin III, human

BRAND INFORMATION

Brand name

Thrombotrol-VF

Active ingredient

Antithrombin III, human

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Thrombotrol-VF.

What is in this leaflet

This leaflet answers some common questions about Thrombotrol®-VF. It does not contain all the available information.

It does not take the place of talking to your doctor.

All medicines have risks and benefits. Your doctor has weighed the risks of you having Thrombotrol®-VF against the benefits they expect it will have for you.

If you have any concerns about having this medicine, ask your doctor.

Keep this leaflet. You may need to read it again.

What Thrombotrol®-VF is used for

This medicine is used to prevent blood clots in people who have an inherited deficiency of antithrombin III in the following circumstances:

  • before surgery
  • during pregnancy
  • during childbirth.

It can also be used to treat blood clots in these patients.

This medicine belongs to a group of medicines called antithrombotic agents. It works by increasing antithrombin III levels and thereby preventing the formation of blood clots.

Some people have an inherited deficiency of antithrombin III and these people may be at risk of spontaneous thrombosis (blood clots) or pulmonary embolism (blood clot which stops blood circulating through the lungs). The risk of these conditions increases with age and in association with surgery, pregnancy and childbirth.

Thrombotrol®-VF contains a concentrated form of antithrombin III which is a protein normally present in the blood and prevents the formation of blood clots.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

Before you are given Thrombotrol®-VF

When you must not have it

Do not have Thrombotrol®-VF if you have an allergy to:

  • any medicine containing antithrombin III
  • any of the ingredients listed at the end of this leaflet
  • any other similar medicines.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Before you start to have it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or plan to become pregnant, are breast-feeding, or have any other medical conditions. Your doctor can discuss the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you are given Thrombotrol®-VF.

About blood products

Thrombotrol® VF is manufactured from human plasma (the liquid component of blood) collected by Australian Red Cross Lifeblood. When products are made from human blood, it is possible that viruses or other substances could be present in the product and cause an illness. These could include different types of viral hepatitis, human immunodeficiency virus (HIV), or parvovirus B19 and theoretically the Creutzfeldt-Jakob Disease (CJD) agent. There could also be other infectious agents which may have not yet been discovered.

To reduce the risk of this happening precautions are taken when manufacturing this product. Strict controls are applied when selecting blood donors and donations. The product is specially treated to remove and kill certain viruses. This special treatment is considered effective against viruses known as enveloped viruses (such as HIV, hepatitis B and C) and the non-enveloped virus, hepatitis A. Effectiveness against the non-enveloped virus parvovirus B19 may be limited.

Despite these measures, the risk of contamination with viruses or other agents cannot be completely eliminated.

Vaccines are available against some of these viruses and your doctor will be able to help you decide whether it is worthwhile having any of those vaccines.

Note: The safety and effectiveness of Thrombotrol®-VF in children and elderly has not been established.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Thrombotrol®-VF may interfere with each other. These include:

  • Heparin. Concurrent use of antithrombin III concentrates may enhance the anticoagulant effect of heparin.

Other medicines may be affected by Thrombotrol®-VF or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor has more information on medicines to be careful with or avoid while taking this medicine.

How to use Thrombotrol®-VF

Thrombotrol®-VF is only available from and given by your doctor. The dose calculated by your doctor is given by intravenous infusion (a slow injection into the vein). Ask your doctor if you have any questions about the way this medicine is administered.

While you are having Thrombotrol®-VF

Things you must do

If you are about to be started on any new medicine, remind your doctor that you are having Thrombotrol®-VF.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are having Thrombotrol®-VF. This medicine helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Furthermore, individual patients may react differently to the same dose of the same medicine. This applies to Thrombotrol®-VF.

Unwanted effects associated with antithrombin III concentrates are not common.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • foul taste in mouth
  • abdominal pain.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • hives
  • fever
  • bruises.

The above side effects include serious side effects that may require medical attention.

If any of the following happen, tell your doctor immediately:

  • dizziness, light-headedness
  • chest tightness
  • shortness of breath.

The above list includes very serious side effects. You may need urgent medical attention.

Tell your doctor if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some people.

Storing Thrombotrol®-VF

Thrombotrol®-VF should be stored in a refrigerator (at 2°C to 8°C) and protected from light. Do not freeze. It should not be used after the expiry date has passed.

Further information

If you want further information about Thrombotrol®-VF and your treatment generally, consult your doctor.

Product description

What it looks like

Thrombotrol®-VF is available as a white powder contained in a glass vial. The product comes with a vial of Water for Injections for reconstitution, and a Mix2Vial™ filter transfer set.

Ingredients

Thrombotrol®-VF contains 1000 International Units (IU) of antithrombin III concentrate (human) as the active ingredient. It also contains:

  • other plasma proteins
  • sodium
  • chloride
  • citrate.

Manufacturer

Thrombotrol®-VF is manufactured in Australia by:

CSL Behring (Australia) Pty Ltd
ABN 48 160 734 761
189-209 Camp Road
Broadmeadows VIC 3047
Australia

Distributor

Australian Red Cross Lifeblood

Date of revision

April 2020

Australian Register Number
AUST R 66736

® Registered trademark of CSL Limited

™ Mix2Vial is a trademark of West Pharmaceutical Services, Inc. or a subsidiary thereof

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Thrombotrol-VF

Active ingredient

Antithrombin III, human

Schedule

Unscheduled

 

Notes

Distributed by Australian Red Cross Lifeblood

1 Name of Medicine

Antithrombin III concentrate (human).

2 Qualitative and Quantitative Composition

Thrombotrol-VF is a sterile, freeze-dried preparation of purified human antithrombin III (ATIII).
Thrombotrol-VF is manufactured from human plasma collected by Australian Red Cross Lifeblood. Each vial of Thrombotrol-VF contains 1000 International Units (IU) of ATIII. The potency assignment has been determined with a standard calibrated against a World Health Organisation (WHO) Antithrombin III reference preparation.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder and diluent for solution for injection.

Powder: white.
Diluent (water for injections): clear, colourless.

4 Clinical Particulars

4.1 Therapeutic Indications

Thrombotrol-VF is indicated in patients with hereditary deficiency of ATIII under the following circumstances:
a) Prophylactic administration for the prevention of thrombosis and pulmonary embolism in surgery, pregnancy and childbirth (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
b) Therapeutic administration in thrombosis or pulmonary embolism.

4.2 Dose and Method of Administration

Each vial of Thrombotrol-VF nominally contains 1000 IU of ATIII.
An individual patient's dose should be determined using the pretreatment and desired plasma ATIII levels, according to the formula shown in Equation 1.
The formula is based on an expected incremental in vivo recovery above baseline levels for ATIII of 2.2% per IU per kg administered. Thus, if a 70 kg individual has a pretreatment ATIII level of 57%, in order to increase plasma ATIII to 120%, the initial Thrombotrol-VF dose required would be [(120 - 57) x 70]/2.2 = 2000 IU.
However, recovery may vary, and initially levels should be determined pre-treatment and 20 minutes post-infusion. Subsequent doses can be calculated based on the recovery of the first dose. These recommendations are intended only as a guide for therapy. The exact loading dose and maintenance intervals should be individualised for each patient, based on the individual's clinical condition, response to therapy and actual plasma ATIII levels achieved.
It is recommended that following an initial dose of Thrombotrol-VF plasma levels of ATIII are monitored at least every 12 hours and before the next infusion of Thrombotrol-VF to maintain plasma ATIII levels at greater than 80%. In some situations, e.g. following surgery, haemorrhage or acute thrombosis, and during intravenous heparin administration, the half-life of ATIII has been reported to be shorter. In such conditions, plasma ATIII levels should be monitored more frequently, and Thrombotrol-VF administered as necessary.
When an infusion of Thrombotrol-VF is indicated for a patient with hereditary deficiency to control an acute thrombotic episode or prevent thrombosis following surgical or obstetrical procedures, it is desirable to raise the ATIII levels to normal. The duration of treatment for which this level needs to be maintained is not established and will depend on the indication for treatment, type and extent of surgery, patient's medical condition, past history and physician's judgement. Concomitant administration of heparin in each of these situations should be based on the medical judgement of the physician.

Reconstitution.

1. Before reconstitution, allow the vials of Thrombotrol-VF and water for injections to reach a temperature between 20°C and 30°C.
2. Remove the caps from the top of the Thrombotrol-VF and water for injections vials.
3. Apply a suitable antiseptic to the exposed part of the rubber stoppers of both Thrombotrol-VF and water for injections and allow to dry.
4. Open the outer package of the Mix2Vial filter transfer set by peeling away the lid. If the seal of the lid is not intact or there are any concerns about the integrity of the Mix2Vial, do not use it but return it to Australian Red Cross Lifeblood. Place the water for injections on a level surface and hold the vial firmly. Take the Mix2Vial together with its outer package and invert it. Push the blue plastic cannula of the Mix2Vial firmly through the rubber stopper of the water for injections.
5. While holding onto the vial of water for injections, carefully remove the outer package from the Mix2Vial, being careful to leave the Mix2Vial attached firmly to the water for injections vial. Ensure that only the package and not the Mix2Vial is removed.
6. With the Thrombotrol-VF vial held firmly on a level surface, invert the water for injections with the Mix2Vial attached and push the transparent plastic cannula end of the Mix2Vial firmly through the Thrombotrol-VF stopper. The water will be drawn into the vial by the vacuum within. In the unlikely event that the vial does not contain a vacuum, do not use the product, but return it to Australian Red Cross Lifeblood.
7. With the water for injections and Thrombotrol-VF vial still attached, gently swirl the product vial to ensure the product is fully dissolved. Avoid excessive frothing. A clear or slightly opalescent solution is usually obtained in 10 minutes or less. The solution should be used immediately as described under Administration.
8. Once the contents of the Thrombotrol-VF vial are completely dissolved, firmly hold both the transparent and blue parts of the Mix2Vial. Unscrew the Mix2Vial into two separate pieces and discard the empty water for injections vial and the blue part of the Mix2Vial in an appropriate waste container.

Note.

The Mix2Vial is intended to filter the contents of a single vial of Thrombotrol-VF only. If multiple vials of Thrombotrol-VF are to be administered, a separate Mix2Vial must be used for each vial.
Do not refrigerate Thrombotrol-VF once it has been reconstituted.

Caution.

The product does not contain an antimicrobial preservative. It must, therefore, be used immediately after reconstitution. Any unused solution should be discarded appropriately. Use in one patient on one occasion only. If a clot or gel forms, do not use the product but return it to Australian Red Cross Lifeblood.

Administration.

1. With the reconstituted Thrombotrol-VF vial upright, attach a plastic disposable syringe to the Mix2Vial (transparent plastic part). Invert the system and draw the reconstituted Thrombotrol-VF into the syringe by pulling the plunger back slowly. One large syringe may be used to pool several vials of reconstituted Thrombotrol-VF.
2. Once the Thrombotrol-VF has been transferred into the syringe, firmly hold the barrel of the syringe (keeping the syringe plunger facing down) and detach the Mix2Vial from the syringe. Discard the Mix2Vial (transparent plastic part) and empty Thrombotrol-VF vial in an appropriate waste container. Fit the syringe to a suitable injection needle to administer the reconstituted Thrombotrol-VF. Do not use the Mix2Vial for injection.
3. Give the dose slowly (approximately 3 mL per minute or as tolerated by the patient) by the intravenous route. When the contents of more than one vial are to be given, it will be convenient to pool the total amount prior to administration in a large syringe or sterile bag. This must be done aseptically.
4. To reduce microbiological hazard, use as soon as practicable after reconstitution/ preparation. The solution must not be stored and, unless reconstitution has been done under aseptic conditions and sterile integrity of the delivery device has been maintained, infusion should be completed within three hours of reconstitution in the case of routine use. Any unused portion remaining in the vial must be discarded appropriately.
The solution must not be added to or mixed with any other fluids to be given, including whole blood.

Monitoring.

It is recommended that ATIII plasma levels be monitored during the treatment period. Functional levels of ATIII in plasma may be measured by amidiolytic assays using chromogenic substrates or by clotting assays.

4.3 Contraindications

Thrombotrol-VF should not be used if there is a history of allergy to this type of product.

4.4 Special Warnings and Precautions for Use

Pathogen safety.

This product is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses and, theoretically, Creutzfeldt-Jakob disease (CJD) agents, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain infectious agents and by testing for the presence of certain viral markers.
In addition, the Thrombotrol-VF manufacturing process includes pasteurisation (60°C for 10 hours) and nanofiltration as dedicated virus inactivation and removal steps to reduce the possibility of virus transmission. The current procedures applied in the manufacture of this product are effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C viruses (HCV), and the non-enveloped virus, hepatitis A (HAV). They are also known to have some effect on the removal of the non-enveloped virus, parvovirus B19.
Despite these measures, such products may still potentially transmit disease. There is also the possibility that other known or unknown infectious agents may be present in such products.
Vaccination (e.g. hepatitis A and hepatitis B) should be considered where appropriate for patients in receipt of medicinal products manufactured from human plasma.

Use in the elderly.

The safety of this product for use in the elderly population has not been established in appropriate studies.

Paediatric use.

Safety and effectiveness in children have not been established. The ATIII level in neonates of parents with hereditary ATIII deficiency should be measured immediately after birth (fatal neonatal thromboembolism, such as aortic thrombi in children of women with hereditary ATIII deficiency, has been reported).
Plasma levels of ATIII are lower in neonates than adults, averaging approximately 60% in normal term infants. ATIII levels in premature infants may be much lower. Low plasma ATIII levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deficiency. It is recommended that testing and treatment with Thrombotrol-VF neonates be discussed with an expert on coagulation.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Concurrent therapy with ATIII concentrates may enhance the anticoagulant effect of heparin (see Section 5.1 Pharmacodynamic Properties).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
The safety of this product for use in human pregnancy has not been established in appropriate studies, therefore it should be given to pregnant women only if clearly needed, taking into consideration that pregnancy confers an increased risk of thromboembolic events in these patients.
The published literature contains several reports relating to the use of ATIII concentrates in ATIII deficient women during pregnancy, at delivery and post-partum. These reports support the clinical efficacy and safety of the product in this indication.
 The safety of this product for use during lactation has not been established in appropriate studies, therefore it should be given to nursing mothers only if clearly needed.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

The clinical study in six asymptomatic subjects with hereditary ATIII deficiency reported only one adverse event of transient rash which occurred 90 minutes after the start of the intravenous infusion and resolved spontaneously within 3 hours.
Adverse reactions associated with other ATIII concentrates include dizziness, chest tightness, foul taste in mouth, abdominal cramps, shortness of breath, light-headedness, hives, fever, and haematoma formation. If adverse reactions are experienced, the infusion rate should be decreased or, if indicated, the infusion should be interrupted until symptoms abate.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

No cases of overdose with ATIII concentrate have been reported.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Antithrombin III, an alpha2-glycoprotein of molecular weight 58,000 daltons, is normally present in human plasma at a concentration of approximately 12.5 mg/dL and is the major plasma inhibitor of thrombin. Inactivation of thrombin by ATIII occurs by formation of a covalent bond resulting in an inactive 1:1 stoichiometric complex between the active serine of thrombin and an arginine reactive site of ATIII. ATIII also inactivates other components of the coagulation cascade including factors IXa, Xa, XIa and XIIa, as well as plasmin.
The neutralisation rate of serine proteases by ATIII is greatly accelerated in the presence of heparin. As the therapeutic antithrombotic effect of heparin is mediated by ATIII, the effectiveness of heparin as an anticoagulant may be reduced in the absence or near absence of ATIII.
The prevalence of the hereditary deficiency of ATIII is estimated to be one per 2000 to 5000 in the general population. In affected individuals, spontaneous episodes of thrombosis and pulmonary embolism may be associated with ATIII levels of 40%-60% of normal. These episodes usually appear after the age of 20, the risk increasing with age in association with surgery, pregnancy and delivery. The frequency of thromboembolic events in hereditary antithrombin III deficiency during pregnancy has been reported to be 70%. Greater than 85% of individuals with hereditary ATIII deficiency have had at least one thrombotic episode by the age of 50 years. Thromboses may be recurrent and in many cases no precipitating factor is identified. In some individuals, treatment with oral anticoagulants leads to a minor increase in endogenous levels of ATIII.

Clinical trials.

In clinical studies, patients with hereditary ATIII deficiency and histories of thromboembolism, treated prophylactically with ATIII concentrates for high thrombotic risk situations (surgery, delivery) have not developed thrombotic complications. Patients with hereditary ATIII deficiency have also been treated therapeutically with ATIII concentrates as well as heparin for major thrombotic or thromboembolic complications, with good results. Treatment with ATIII concentrates reversed heparin resistance in patients with hereditary ATIII deficiency being treated for thrombosis or thromboembolism.
CSL has performed a pharmacokinetic and safety clinical study in six asymptomatic subjects with hereditary deficiency of ATIII. The study used the ATIII product prior to the introduction of a virus filtration (nanofiltration) step. The product supplied with this leaflet, Thrombotrol-VF, includes a nanofiltration step in the manufacturing process to enhance viral safety. This product has been the subject of extensive biochemical characterisation which has demonstrated that the active ingredient is equivalent to, and the concentrate more pure than the product investigated in the clinical study. The latter contained higher amounts of histidine-rich glycoprotein, platelet factor 4 and factor XI, than Thrombotrol-VF. The influence of these proteins on the pharmacokinetics of ATIII is unknown. The pharmacokinetic parameters from this clinical study are described (see Section 5.2).
During the clinical investigation none of the 6 subjects monitored for 9 months after receiving a single dose showed evidence of seroconversion to the following viruses: human immunodeficiency virus (HIV-1, HIV-2), hepatitis A, B or C, cytomegalovirus, Epstein-Barr virus, human herpes virus 6 and human parvovirus B19.

5.2 Pharmacokinetic Properties

In the pharmacokinetic and safety clinical study, six volunteers with asymptomatic congenital ATIII deficiency were administered a single, variable dose of Thrombotrol (ATIII product prior to the introduction of a virus filtration step). The mean in vivo recovery of ATIII was 3.1% per IU per kg administered based on immunological ATIII assay, and 2.2% per IU per kg administered based on functional ATIII assay. The half-life (t½) of ATIII was 3.2 days based on immunological assays and 2.8 days based on functional assays of ATIII. These values are similar to the pharmacokinetic parameters reported for other ATIII concentrates in the literature.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies have been conducted with Thrombotrol-VF.

Carcinogenicity.

No carcinogenicity studies have been conducted with Thrombotrol-VF.

6 Pharmaceutical Particulars

6.1 List of Excipients

Human plasma proteins, sodium, citrate, chloride.

6.2 Incompatibilities

The reconstituted solution must not be added to or mixed with any other fluids to be given, including whole blood.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the carton packaging.

Reconstituted product.

The product does not contain an antimicrobial preservative. It must, therefore, be used immediately after reconstitution.

6.4 Special Precautions for Storage

Thrombotrol-VF should be stored at 2°C to 8°C. (Refrigerate. Do not freeze). Protect from light. Do not use after the expiry date.

Reconstituted product.

Do not refrigerate Thrombotrol-VF once it has been reconstituted.

6.5 Nature and Contents of Container

Each Thrombotrol-VF single pack contains:
One 50 mL glass vial of Thrombotrol-VF containing 1000 IU of ATIII, with a rubber stopper closed with an aluminum seal and a plastic flip-top cap.
One glass vial of 20 mL water for injections, with a rubber stopper closed with an aluminium seal and a plastic flip-top cap.
One Mix2Vial filter transfer set.
Thrombotrol-VF is packaged in latex free materials.

6.6 Special Precautions for Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

CAS number.

52014-67-2.

7 Medicine Schedule (Poisons Standard)

Unscheduled.

Summary Table of Changes