ONDEXXYA Powder for solution for infusion Ref.[27699] Active ingredients: Andexanet alfa

Restricted to hospital use only.

Posology

Andexanet alfa is administered as an intravenous bolus at a target rate of approximately 30 mg/min over 15 minutes (low dose) or 30 minutes (high dose), followed by administration of a continuous infusion of 4 mg/min (low dose) or 8 mg/min (high dose) for 120 minutes (see table 1). Posology of andexanet alfa is based upon PK/PD-modelling and simulation exercises (see sections 5.1 and 5.2).

Table 1. Dosing regimens:

Reversal of apixaban

The recommended dose regimen of Ondexxya is based on the dose of apixaban the patient is taking at the time of anticoagulation reversal, as well as on the time since the patient’s last dose of apixaban (see table 2). If the strength of the last dose of anticoagulant or the interval between the last dosage and the bleeding episode are unknown, no dose recommendation is available. Measurement of baseline anti-FXa-level should support the clinical decision of starting treatment (if level is available in an acceptable timely frame).

Table 2. Summary of dosing for reversal of apixaban:

Restarting antithrombotic therapy

Following administration of Ondexxya and cessation of a major bleed, re-anticoagulation should be considered to prevent thrombotic events due to the patient’s underlying medical condition. Antithrombotic therapy can be re-initiated as soon as medically indicated following treatment if the patient is clinically stable and adequate haemostasis has been achieved. Medical judgement should balance the benefits of anticoagulation with the risks of re-bleeding (see section 4.4).

Special populations

Elderly patients (aged 65 years and over)

No dose adjustment is required in elderly patients (see section 5.2).

Renal impairment

The effect of renal impairment on andexanet alfa exposure levels has not been evaluated. Based on the existing data on clearance, no dose adjustment is recommended.

Hepatic impairment

Based on the existing data on clearance of andexanet alfa, no dose adjustment is recommended. The safety and efficacy have not been studied in patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of andexanet alfa in children and adolescents have not been established. No data are available.

Method of administration

Intravenous use

After an appropriate number of vials of Ondexxya has been reconstituted, the reconstituted solution (10 mg/mL) without further dilution is transferred to sterile large volume syringes in case a syringe pump is used for administration or to suitable empty intravenous bags comprised of polyolefin (PO) or polyvinyl chloride (PVC) material (see section 6.6). Prior to administration by IV infusion a 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein-binding filter should be used.

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

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

There is no clinical experience with overdose of andexanet alfa. No dose-limiting toxicities have been observed during clinical trials.

Vial (unopened): Four years stored at 2°C to 8°C.

Reconstituted medicinal product: Chemical and physical in-use stability has been demonstrated for 16 hours at 2°C to 8°C in the primary packaging vial. If needed, the reconstituted solution once transferred into the IV bag can be stored for an additional eight hours at room temperature. From a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user

Store in a refrigerator (2°C to 8°C).

Do not freeze.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Powder in a 20 mL vial (Type I glass) with a stopper (butyl rubber).

Pack size of four or five vials.

Not all pack sizes may be marketed.

Reconstitution:

The following are needed before starting reconstitution:

• Calculated number of vials (see section 4.2).
• Same number of 20 mL (or larger) solvent syringes equipped with a 20 gauge (or larger) needle.
• Alcohol swabs.
• Large (50 mL or larger) sterile syringe. If a syringe pump is used for administration, multiple syringes should be used to contain the final volume of reconstituted product.
• Intravenous bags of polyolefin (PO) or polyvinyl chloride (PVC) material (150 mL or larger) to contain the final volume of reconstituted product (if administration is performed with IV bags).
• Water for injections.
• 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein-binding filter.

Andexanet alfa does not need to be brought to room temperature before reconstitution or administration to the patient. Aseptic technique during the reconstitution procedure should be used.

Each vial is reconstituted according to the following instructions:

1. Remove the flip-top from each vial.
2. Wipe the rubber stopper of each vial with an alcohol swab.
3. Using a 20 mL (or larger) syringe and a 20 gauge (or larger) needle, withdraw 20 mL of water for injections.
4. Insert the syringe needle through the centre of the rubber stopper.
5. Push the plunger down to slowly inject the 20 mL of water for injections into the vial, directing the stream toward the inside wall of the vial to minimise foaming.
6. Gently swirl each vial, until all of the powder is completely dissolved. DO NOT SHAKE the vials, as this can lead to foaming. The dissolution time for each vial is approximately three to five minutes.
7. The reconstituted solution should be inspected for particulate matter and/or discolouration prior to administration. Do not use if opaque particles or discolouration are present.
8. For the most efficient reconstitution of the needed dose, and to minimise errors, inject each vial needed with 20 mL of water for injections before proceeding to the next step.
9. Use within eight hours after reconstitution when stored at room temperature.

Administration using a syringe pump:

1. Once all required vials are reconstituted, the reconstituted solution is withdrawn from each vial, using the large volume (50 mL or larger) syringe equipped with a 20 gauge (or larger) needle.
2. The bolus and infusion are prepared in separate large volume syringes.
3. Due to the additional volume, the high dose bolus and infusion have to be further separated into additional syringes (two syringes apiece for bolus and infusion).
4. To prevent the inadvertent transfer of air, be careful to hold the syringe needle up, and do not set the syringe down between multiple withdrawals from vials.
5. Attach ancillary equipment (i.e., extension tubing, 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein-binding filter, syringe pump) in preparation for administration.
6. Administer the reconstituted solution at the appropriate rate.
7. Discard all used syringes, needles, and vials, including any unused portion of reconstituted solution.

Administration using intravenous bags:

1. Once all required vials are reconstituted, withdraw the reconstituted solution from each vial, using the large volume (50 mL or larger) syringe equipped with a 20 gauge (or larger) needle.
2. Transfer the reconstituted solution from the syringe into an appropriate IV bag.
3. Repeat steps 1 and 2 as necessary to transfer the complete volume of the bolus and the infusion into a PO or PVC IV bags.
4. It is recommended that the bolus and infusion be split into two separate bags to ensure the correct administration rate. Although it is also permissible to use one PO or PVC IV bag for the bolus and infusion, the correct infusion rate must be ensured when switching from the bolus to the infusion.
5. Attach ancillary equipment (i.e., extension tubing, 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein-binding filter, IV pump) in preparation for administration.
6. Administer the reconstituted solution at the appropriate rate.

Disposal:

All used syringes, needles, and vials, including any unused portion of reconstituted solution, should be disposed of in accordance with local requirements.