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

Limitations of use

Clinical efficacy is based upon reversal of anti-FXa-activity in healthy volunteers and bleeding patients dosed with apixaban or rivaroxaban. Andexanet alfa is not suitable for pre-treatment of urgent surgery. Use for edoxaban or enoxaparin-reversal is not recommended due to lack of data. Andexanet alfa will not reverse the effects of non-FXa inhibitors (see section 5.1).

Treatment monitoring should be based mainly on clinical parameters indicative of appropriate response (i.e., achievement of haemostasis), lack of efficacy (i.e., re-bleeding), and adverse events (i.e., thromboembolic events). Treatment monitoring of andexanet alfa should not be based on antiFXa-activity. Commercial anti-FXa-activity assays are unsuitable for measuring anti-FXa activity following administration of andexanet alfa as these assays result in erroneously elevated anti-FXa activity levels, thereby causing a substantial underestimation of the reversal activity of andexanet alfa.

Dosage recommendation is based upon data-modelling in healthy volunteers. Validation has not been successful, yet. Data from bleeding patients are limited. Data suggest higher risk of thrombosis for patients receiving the higher dose of andexanet, previous lower dose of the anti-FXa inhibitor, and patients on rivaroxaban.

In study 14-505, intracranial haemorrhage (ICH) patients (GCS >7 and haematoma volume <60 mL) have been included. Treatment of patients with more severe ICH with andexanet alfa has not been studied.

Thrombotic events

Thrombotic events have been reported following treatment with andexanet alfa (see sections 4.8 and 5.1). Patients being treated with FXa inhibitor therapy have underlying disease states that predispose them to thrombotic events. Reversing FXa inhibitor therapy exposes patients to the thrombotic risk of their underlying disease. In addition, independent pro-coagulant effect of andexanet alfa, mediated by inhibition of tissue factor pathway inhibitor (TFPI), has been demonstrated, which may pose a risk of developing thrombosis. Duration of this effect in bleeding patients is not known.

Laboratory parameters as anti-FXa activity, endogenous thrombotic potential (ETP), or markers of thrombosis might not be reliable for guidance. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate after completion of treatment.

In healthy volunteers, dose-dependent increases in coagulation markers F1+2, TAT, and D-dimer, and dose-dependent decreases in TFPI, after administration of andexanet alfa were observed, but no thromboembolic events were reported. These markers were not measured in patients enrolled in study 14-505, but thromboembolic events have been observed (see section 4.8 and 5.1). Monitoring for signs and symptoms of thrombosis is, therefore, strongly recommended.

Use of andexanet alfa in conjunction with other supportive measures

Andexanet alfa can be used in conjunction with standard haemostatic supportive measures, which should be considered as medically appropriate.

The safety of andexanet alfa has not been evaluated in patients who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood within seven days prior to the bleeding event, as they were excluded from clinical trials. Pro-coagulant factor treatments (e.g., 3- or 4-factor prothrombin complex concentrate (PCC)/activated PCC, recombinant factor VIIa, fresh frozen plasma) and whole blood should be avoided unless absolutely required, due to lack of data in combination with these treatments.

Interaction with heparin

Use of andexanet prior to heparinization e.g. during surgery should be avoided as andexanet causes unresponsiveness to heparin. Use of andexanet as an antidote for heparin or low-molecular weight heparin has not been evaluated and is not recommended (refer to section 4.5).

Infusion-related reactions

In case of mild or moderate infusion reactions, careful observation may be sufficient. For moderate symptoms, consideration may be given to a brief interruption or slowing of the infusion with resumption of the infusion after symptoms subside. Diphenhydramine may be administered.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

No interaction studies with andexanet alfa have been performed.

In vitro data suggest interaction of andexanet alfa with the heparin- anti-thrombin III (ATIII) complex and neutralization of the anticoagulant effect of heparin. Off-label use of andexanet alfa pre-surgery with intended heparin-anticoagulation has been reported to cause unresponsiveness to heparin (refer to section 4.4). Use of andexanet as an antidote for heparin or low-molecular weight heparin has not been evaluated and is not recommended.

Pregnancy

There are no data from the use of andexanet alfa in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Andexanet alfa is not recommended during pregnancy or in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether andexanet alfa is excreted in human milk. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with andexanet alfa.

Fertility

There are no data on the effects of andexanet alfa on human fertility.

Andexanet alfa has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The safety of andexanet alfa has been evaluated in clinical trials including 417 healthy subjects administered an FXa inhibitor, as well as in 419 patients in a Phase IIIb/IV trial (study 14-505), who had acute major bleeding and were under treatment with an FXa inhibitor (apixaban and rivaroxaban).

In clinical studies in healthy subjects who were administered a FXa inhibitor and then received andexanet alfa, the frequency of adverse reactions was similar in the andexanet alfa-treated group (16.8%) and in the placebo treated group (12.2%). The most frequently observed adverse reactions were mild or moderate infusion-related reactions comprising symptoms such as flushing, feeling hot, cough, dysgeusia, and dyspnoea occurring within a few minutes to a few hours of the infusion. Among the healthy subjects studied, women experienced more adverse reactions (mainly infusionrelated reactions) than men.

In the healthy subject trials, elevations >2 x ULN in D-dimer and prothrombin fragments F1+2 were frequently observed. These elevations were maintained between several hours to a few days following administration, but no thrombotic events were reported.

In patients with major bleedings thrombosis-markers have not been investigated since bleeding can interfere with the thrombosis marker results. Thromboses and thromboembolic events have commonly been documented.

Tabulated list of adverse reactions

Table 4 provides the list of adverse reactions in patients with major bleeds from study 14-505 including 419 patients on apixaban and rivaroxaban with acute major bleeding treated with andexanet alfa. The adverse reactions are classified by system organ class (SOC) and frequency, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); or not known (cannot be estimated from available data).

Table 4. List of adverse reactions in patients with major bleeds:

^a reported signs/symptoms (rigors, chills, hypertension, oxygen desaturation, agitation and confusion) were transient and mild to moderate in severity.

Description of selected adverse reactions

Based on data from 419 patients from the Phase IIIb/IV study 14-505 treated with apixaban and rivaroxaban and experiencing an acute major bleeding episode, two patients (0.5%) experienced an infusion-related reaction, neither of which was assessed as severe (1 moderate; 1 mild).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.