ONDEXXYA 200 MG POWDER FOR SOLUTION FOR INFUSION

2. What you need to know before you are given Ondexxya

Do not use Ondexxya:

• if you are allergic to andexanet alfa or any of the other ingredients of this medicine (listed in section 6).
• if you are allergic to hamster proteins
• if you are receiving heparin

Warnings and precautions

Reversal of the factor Xa inhibitor effect with Ondexxya may increase the risk of blood clots. After treatment with Ondexxya, your doctor will decide when to restart anticoagulant treatment.

The potential procoagulant effect of andexanet alfa may carry an additional risk of developing thrombosis.

If you experience a side effect during administration of Ondexxya by intravenous infusion, your doctor may decide to reduce the infusion rate or stop treatment. Your doctor may give you an antihistamine to alleviate side effects (see section 4).

Ondexxya should be avoided if you are scheduled for surgery that requires anticoagulation with heparin.

Children and adolescents

No data are available on the use of Ondexxya in children and adolescents.

Other medicines and Ondexxya

Tell your doctor if you are taking, have recently taken or might take any other medicines.

This medicine has only been developed to reverse the effects of factor Xa inhibitor medicines. It is unlikely that Ondexxya will interfere with the effect of other medicines, or that other medicines will interfere with Ondexxya.

Treatment with Ondexxya should be avoided if anticoagulation with heparin is required. Ondexxya causes lack of response to heparin.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor.

Ondexxya is not recommended during pregnancy or in women of childbearing potential who are not using contraception.

Do not breast-feed your child while taking this medicine. It is not known whether andexanet alfa passes into breast milk.

Driving and using machines

It is unlikely that this medicine will affect your ability to drive or use machines.

3. How Ondexxya is given

This medicine is for hospital use only.

Your doctor or nurse will give you this medicine by injection or infusion into a vein.

Your doctor or nurse will decide the dose of medicine you need. This is based on the anticoagulant medicine you are taking, as well as the dose and time since you last took the anticoagulant.

After administration of Ondexxya, your doctor will decide when to restart anticoagulant treatment.

At the end of this leaflet are detailed instructions for your doctor or nurse on how to administer Ondexxya (see "Instructions for use").

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

4. Possible side effects

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

List of side effects observed in people with bleeding

Common(may affect up to 1 in 10 people)

• Stroke
• Myocardial infarction
• Blood clots in legs, arms, lungs or brain
• Fever

Uncommon(may affect up to 1 in 100 people)

• Mini-stroke
• Cardiac arrest
• Signs/symptoms of infusion-related reactions, such as chills, high blood pressure, difficulty breathing, confusion or agitation.

Reporting of side effects

If you experience any side effects, talk to your doctor or nurse, even if they are not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Ondexxya

This medicine is stored in the hospital, and these instructions are intended only for hospital personnel.

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 vial and carton after CAD/EXP.

The expiry date is the last day of the month shown.

Store in a refrigerator (between 2°C and 8°C).

Do not freeze.

Once reconstituted, Ondexxya is for immediate use.

6. Container Contents and Additional Information

Ondexxya Composition

• The active ingredient is andexanet alfa.
• The other components are tris base, tris hydrochloride, L-arginine hydrochloride, sucrose, mannitol, and polysorbate 80.

Product Appearance and Container Contents

Ondexxya is supplied in glass vials as a white to off-white powder for solution for infusion, which is reconstituted (dissolved) before use. The reconstituted solution is clear, colorless, or slightly yellow.

Each container contains four or five vials.

Only some pack sizes may be marketed.

Marketing Authorization Holder

AstraZeneca AB

SE-151 85 Södertälje

Sweden

Manufacturer

Alexion Pharma International Operations Limited

Alexion Dublin Manufacturing Facility

College Business and Technology Park

Blanchardstown Rd North

Dublin D15 R925

Ireland

You can request more information about this medicinal product by contacting the local representative of the marketing authorization holder:

Date of Last Revision of this Leaflet:

This medicinal product has been authorized with a "conditional approval". This type of approval means that more information on this medicinal product is expected.

The European Medicines Agency will review the new information on this medicinal product at least once a year and this leaflet will be updated as necessary.

Other Sources of Information

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

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This information is intended only for healthcare professionals:

Andexanet has not been shown to be effective for, and is not indicated for, the treatment of bleeding associated with any factor Xa inhibitor other than rivaroxaban or apixaban. It also does not reverse the effects of non-factor Xa inhibitors.

Posology and Method of Administration:

Andexanet alfa is administered as an intravenous (IV) bolus at a target rate of approximately 30 mg/min for 15 (low dose) or 30 minutes (high dose), followed immediately by a continuous IV infusion of 4 mg (low dose) or 8 mg (high dose) per minute for 120 minutes (see Table 1).

Table 1: Administration Schedule

The dose recommendations are based on the effects of andexanet alfa in healthy volunteers who received a direct factor Xa inhibitor, and on the ability to reverse anti-factor Xa activity levels. The dose was used in a study with patients with acute major bleeding.

Reversal of Apixaban

The recommended administration schedule for andexanet alfa depends on the dose of apixaban the patient is taking at the time of anticoagulant reversal, as well as the time since the last dose of apixaban (see Table 2). If the concentration of the last dose of anticoagulant or the interval between the last dose and the bleeding episode is unknown, no dose recommendation is available. The measurement of the baseline anti-factor Xa level should support the clinical decision to initiate treatment (if such a level is available within an acceptable timeframe).

Table 2: Summary of Dosing for Reversal of Apixaban

Reversal of Rivaroxaban

The recommended administration schedule for andexanet alfa depends on the dose of rivaroxaban the patient is taking at the time of anticoagulant reversal, as well as the time since the last dose of rivaroxaban (see Table 3). If the concentration of the last dose of anticoagulant or the interval between the last dose and the bleeding episode is unknown, no dose recommendation is available. The measurement of the baseline anti-factor Xa level should support the clinical decision to initiate treatment (if such a level is available within an acceptable timeframe).

Table 3: Summary of Dosing for Reversal of Rivaroxaban

Patients treated with a factor Xa inhibitor have an underlying condition that predisposes them to thromboembolic events. Treatment for reversal of a factor Xa inhibitor exposes patients to the thrombotic risk of their underlying condition. To reduce this risk, consideration should be given to resuming anticoagulant treatment as soon as medically appropriate.

Instructions for Use:

After reconstituting andexanet alfa, the 10 mg/ml solution is transferred without further dilution to large-volume sterile syringes if a syringe pump is used for administration or to empty intravenous infusion bags made of polyolefin (PO) or polyvinyl chloride (PVC) suitable for the administration. Before IV administration, an in-line filter with low protein binding of polyethersulfone (PES) or equivalent of 0.2 or 0.22 microns should be used.

The chemical and physical in-use stability of the reconstituted solutions has been demonstrated for at least eight hours at 25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, it is the responsibility of the user to ensure the storage times and conditions before use.

Reconstitution

Before starting reconstitution, you need to have:

• The number of vials calculated as indicated in Table 1.
• The same number of syringes with 20 ml (or more) of solvent and a 20-gauge (or larger) needle.
• Alcohol swabs.
• A large sterile syringe (50 ml or more). If administration is done with a syringe pump, multiple syringes should be used to contain the final volume of the reconstituted product.
• Intravenous infusion bags made of polyolefin (PO) or polyvinyl chloride (PVC) (150 ml or more) to contain the volume of the reconstituted medicinal product (if administration is done with intravenous infusion bags).
• Water for injections
• An in-line filter with low protein binding of polyethersulfone (PES) or equivalent of 0.2 or 0.22 microns.

It is not necessary for andexanet alfa to reach room temperature before reconstitution or administration to the patient. Use an aseptic technique during reconstitution.

Reconstitute each vial by following the instructions below:

1. Remove the caps from all the vials.
2. Wipe the rubber stoppers of the vials with an alcohol swab.
3. Draw 20 ml of water for injections with a 20 ml (or larger) syringe and a 20-gauge (or larger) needle.
4. Pierce the center of the rubber stopper with the needle of the syringe.
5. Press the plunger down to slowly inject the 20 ml of water for injections into the vial. Direct the stream to the inner wall of the vial to minimize foam generation.
6. Gently swirl each vial with circular movements until all the powder is dissolved. DO NOT SHAKE the vials as this may generate foam. The dissolution time for each vial is approximately 3 to 5 minutes.
7. Before administration, check if the solution contains particles or has changed color. Do not use it if it contains opaque particles or has changed color.
8. To achieve effective reconstitution of the required dose and minimize errors, inject 20 ml of water for injections into each vial that will be needed before proceeding to the next step.
9. Use andexanet alfa within eight hours after reconstitution if stored at room temperature.

Administration with a Syringe Pump

1. After reconstituting all the required vials, withdraw the reconstituted solution from each vial with a large-volume syringe (50 ml or more) with a 20-gauge (or larger) needle.
2. Prepare the bolus and infusion in two separate large-volume syringes.
3. Due to the additional volume, both the high-dose bolus and infusion should be divided into additional syringes (two syringes for each).
4. To avoid unintentional air transfer, hold the needle with the syringe upright and do not lower the syringe between withdrawals from the vials.
5. Assemble the necessary ancillary equipment (e.g., extension tubes, in-line filter with low protein binding of polyethersulfone (PES) or equivalent of 0.2 or 0.22 microns, continuous infusion pump) for administration.
6. Administer the reconstituted solution at the appropriate rate.
7. Discard used syringes, needles, and vials, as well as any unused reconstituted solution.

Administration using Intravenous Infusion Bags

1. After reconstituting all the required vials, withdraw the reconstituted solution from each vial with a large-volume syringe (50 ml or more) with a 20-gauge (or larger) needle.
2. Transfer the reconstituted solution from the syringe to the appropriate intravenous infusion bags made of polyolefin (PO) or polyvinyl chloride (PVC).
3. Repeat steps 1 and 2 as needed to transfer all the volume of the bolus and infusion to intravenous infusion bags made of PO or PVC.
4. It is recommended to divide the bolus and infusion into two separate bags to ensure the correct administration rate. However, it is also permissible to use one intravenous infusion bag made of PO or PVC for the bolus and infusion.
5. Assemble the necessary ancillary equipment (e.g., extension tubes, in-line filter with low protein binding of polyethersulfone (PES) or equivalent of 0.2 or 0.22 microns, IV pump) for administration.
6. Administer the reconstituted solution at the appropriate rate.

Disposal

All used syringes, needles, and vials, as well as any unused reconstituted solution, should be disposed of in accordance with local regulations.