Ondexxya - patient leaflet, side effects, dosage

Patient leaflet - Ondexxya

B. PACKAGE LEAFLET

Package Leaflet: Information for the patient and user

Ondexxya 200 mg powder for solution for infusion andexanet alfa

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully, because it contains important information for you. Please note this medicine is mainly used in emergency situations, and the doctor will have decided that you needed it.

Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or nurse.
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

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

1. What Ondexxya is and what it is used for

Ondexxya contains the active ingredient andexanet alfa. It reverses the effects of certain anticoagulants called factor Xa inhibitors (apixaban or rivaroxaban). Factor Xa inhibitors are given to prevent clots in your blood vessels. Your doctor may decide to give you Ondexxya to rapidly reverse the effects of the anticoagulant in case of a life-threatening or uncontrolled bleeding situation.

2. What you need to know before you receive 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

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

An independent pro-coagulant effect of andexanet alfa may pose an additional risk of developing thrombosis.

If you suffer side effects when you are being given Ondexxya by infusion (drip), your doctor may decide to slow down or pause your treatment. Your doctor may give you an antihistamine medicine to help with any side effects (see section 4).

If a surgery is planned for you which requires anticoagulation with heparin, Ondexxya should be avoided.

Children and adolescents

There is no information 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 been designed to reverse the effects of factor Xa inhibitor medicines only. It is unlikely that Ondexxya will influence the effect of other medicines or that other medicines will influence Ondexxya.

Ondexxya-treatment should be avoided if anticoagulation with heparin might become necessary. Ondexxya causes unresponsiveness to heparin.

Pregnancy and breast-feeding

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

Ondexxya is not recommended during pregnancy or if you have the potential to become pregnant and are not using birth control.

Do not breast-feed your child while you are taking this medicine. It is unknown if andexanet alfa is excreted in human milk.

Driving and using machines

This medicine is unlikely to affect your ability to drive and use machines.

3. How Ondexxya is used

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 work out the dose of this medicine that you need. This is based on the specific anticoagulant medicine you take as well as on the dose and the time since your last dose of anticoagulant medicine.

After you have received Ondexxya, your doctor will decide when to restart your anticoagulant treatment.

Detailed instructions for your doctor or nurse on how to give Ondexxya are given at the end of this package leaflet (see ‘Handling instructions’).

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.

The most common side effects associated with Ondexxya in clinical trials of healthy people were infusion-related reactions with usually mild symptoms such as flushing or feeling hot (very common side effects which may affect more than 1 in 10 people). Headache, cough, or shortness of breath (common side effects which may affect up to 1 in 10 people) happened within a few minutes to a few hours of the infusion. In clinical trials of patients with life-threatening bleeding, fever and stroke may affect up to 1 in 10 people; transient ischaemic attack (TIA), heart attack, and blood clots in the legs or lungs may affect up to 1 in 100 people (uncommon side effects).

List of possible side effects

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

flushing or feeling hot
effects on blood clotting markers: some markers which affect blood clotting were increased for a little while and then returned to normal. There were no blood clots in these healthy people.

Common (may affect up to 1 in 10 people)

hives
dizziness
rapid or irregular heartbeat
stomach pain or discomfort
dry mouth
disturbance of taste
nausea (feeling sick)
chest discomfort
feeling cold
excessive sweating
itching
back pain
muscle spasms

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed inBy reporting side effects, you can help provide more information on the safety of this medicine.

5. How Ondexxya is stored

This medicine will be stored in the hospital, and these instructions are intended for hospital staff only. 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 the carton after

EXP. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C to 8°C).

Do not freeze.

Once reconstituted, Ondexxya is for immediate use.

6. Contents of the pack and other information What Ondexxya contains

The active substance is andexanet alfa.
The other ingredients are Tris base, Tris hydrochloride, L-arginine hydrochloride, sucrose, mannitol, and polysorbate 80.

What Ondexxya looks like and contents of the pack

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 a clear, colourless, or slightly yellow solution.

Each pack contains four vials.

Marketing Authorisation Holder

Alexion Europe SAS

103–105 rue Anatole France

92300 Levallois-Perret

France

Manufacturer

Alexion Pharma International Operations Unlimited Company

Alexion Dublin Manufacturing Facility

College Business and Technology Park

Blanchardstown Rd North

Dublin D15 R925

Ireland

This leaflet was last revised in.

This medicine has been given ‘conditional approval’. This means that there is more evidence to come about this medicine.

The European Medicines Agency will review new information on this medicine at least every year and this leaflet will be updated as necessary.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:

The following information is intended for healthcare professionals only.

Andexanet has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any FXa inhibitor other than rivaroxaban or apixaban. Also, it will not reverse the effects of non-FXa inhibitors.

Dosage and administration

Andexanet alfa is administered as an intravenous (IV) bolus at a target rate of approximately 30 mg/min over 15 (low dose) or 30 minutes (high dose), immediately 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).

Table 1: Dosing regimens

	Initial intravenous bolus	Continuous intravenous infusion	Total number of 200 mg vials needed
Low dose	400 mg at a target rate of 30 mg/min	4 mg/min for 120 minutes (480 mg)	5
High dose	800 mg at a target rate of 30 mg/min	8 mg/min for 120 minutes (960 mg)	9
Dosage recommendations have been defined from the effects of andexanet alfa in			healthy

volunteers administered a direct FXa inhibitor and from the ability to reverse the levels of anti-FXa activity. The posology was confirmed in a study in patients with acute major bleeding.

Reversal of apixaban

The recommended dose regimen of andexanet alfa 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).

Table 2: Summary of dosing for reversal of apixaban

FXa inhibitor	FXa inhibitor last dose	Timing of FXa inhibitor last dose before andexanet alfa initiation
		< 8 hours or unknown	> 8 hours
Apixaban	< 5 mg	Low dose	Low dose
	> 5 mg/ Unknown	High dose

Reversal of rivaroxaban

The recommended dose regimen of andexanet alfa is based on the dose of rivaroxaban the patient is taking at the time of anticoagulation reversal, as well as on the time since the patient’s last dose of rivaroxaban (see table 3).

Table 3: Summary of dosing for reversal of rivaroxaban

FXa inhibitor	FXa inhibitor last dose	Timing of FXa inhibitor last dose before andexanet alfa initiation
		< 8 hours or unknown	> 8 hours
Rivaroxaban	< 10 mg	Low dose	Low dose
	> 10 mg/ Unknown	High dose

Patients being treated with FXa inhibitor therapy have underlying disease states that predispose them to thromboembolic events. Reversing FXa inhibitor therapy exposes patients to the thrombotic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate.

Handling instructions

Andexanet alfa is to be reconstituted and the 10 mg/mL solution then transferred without further dilution to sterile large volume syringes in case a syringe pump is used for administration or to suitable empty IV bags comprised of polyolefin (PO) or polyvinyl chloride (PVC) material. 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.

For reconstituted solutions, chemical and physical in-use stability have been demonstrated for at least eight hours at 25°C. From a microbiological point of view, once opened, 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.

Reconstitution

Before starting reconstitution, you will need the following:

Calculated number of vials as given in table 1.
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 administration is done with a syringe pump, 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 done with an IV bag).
Water for injection
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. Use aseptic technique during the reconstitution procedure.

Reconstitute each vial 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 injection.
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 andexanet alfa within eight hours after reconstitution when stored at room temperature.

Administration using a syringe pump

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. Prepare the bolus and infusion in separate large volume syringes.
3. Due to the additional volume, the high dose bolus and infusion will need 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 appropriate IV bags.
3. Repeat steps 1 and 2 as necessary to transfer the complete volume of the bolus and the infusion into 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.