Andexanet alfa interacts in the following cases:
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.
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.
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.
There are no data from the use of andexanet alfa in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Andexanet alfa is not recommended during pregnancy or in women of childbearing potential not using contraception.
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.
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.
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.
The table below 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).
List of adverse reactions in patients with major bleeds:
| System Organ Class | Very common ≥1/10 | Common ≥1/100 to <1/10 | Uncommon ≥1/1,000 to <1/100 |
|---|---|---|---|
| Nervous system disorders | Cerebrovascular accident Ischaemic stroke | Cerebral infarction Transient ischaemic attack | |
| Cardiac disorders | Acute myocardial infarction Myocardial infarction | Cardiac arrest | |
| Vascular disorders | Deep vein thrombosis | Iliac artery occlusion | |
| Respiratory, thoracic and mediastinal disorders | Pulmonary embolism | ||
| General disorders and administrative site conditions | Pyrexia | ||
| Injury, poisoning and procedural complications | Infusion related reactiona |
a reported signs/symptoms (rigors, chills, hypertension, oxygen desaturation, agitation and confusion) were transient and mild to moderate in severity.
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).
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