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ONDEXXYA is a brand name for Andexanet Alfa, supplied as a powder for solution. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: ONDEXXYA (andexanet alfa) is indicated for: • adult patients treated with FXa inhibitors (rivaroxaban or apixaban) when rapid reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. ONDEXXYA has not been shown to be effective for, and is not indicated for, the treatment of bleeding…
Verbatim from this product's HC label. Tap a section to expand.
1 Dosing Considerations For intravenous (IV) use only. Patients being treated with FXa inhibitors 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 (see 7 WARNINGS AND PRECAUTIONS, Hematologic). 2 Recommended Dose and Dosage Adjustment • Select the appropriate dosing regimen following the guidance in Table 1.
• Administer ONDEXXYA as an IV bolus followed by administration of a continuous infusion as per Table 2. The recommended dosing of ONDEXXYA is based on the specific FXa inhibitor, dose of FXa inhibitor, and time since the patient’s last dose of FXa inhibitor (see Table 1).
Table 1 - ONDEXXYA Dose Based on Rivaroxaban or Apixaban Dose and Timing of Last Dose of FXa Inhibitor before ONDEXXYA Initiation FXa Inhibitor FXa Inhibitor Last Dose < 8 Hours or Unknown ≥ 8 Hours Rivaroxaban ≤ 10 mg Low Dose Low Dose > 10 mg or Unknown High Dose Apixaban ≤ 5 mg Low Dose > 5 mg or Unknown High Dose The low- and high-dose regimens are described in Table 2.
Table 2 - ONDEXXYA dosing regimens Dose* Initial IV Bolus Follow-On IV Infusion** Total number of 200 mg vials Low Dose 400 mg at a target rate of 30 mg/min 4 mg/min for 120 minutes (480 mg) 5 (2 vials bolus + 3 vials infusion) High Dose 800 mg at a target rate of 30 mg/min 8 mg/min for 120 minutes (960 mg) 9 (4 vials bolus + 5 vials infusion) * The safety and efficacy of more than one dose have not been evaluated.
** Because the recommended infusion doses are lower than the andexanet alfa content of the vials, there will be a small amount of solution remaining in the bag after completion of the infusion. IV=intravenous infusion ONDEXXYA® (andexanet alfa) Page 6 of 32 Special Populations Pediatrics (< 18 years of age): Health Canada has not authorized an indication for pediatric use.
Geriatrics (≥ 65 years of age):
No dose adjustment is recommended for elderly patients (≥ 65 years of age) (see 7 WARNINGS AND PRECAUTIONS and 10 CLINICAL PHARMACOLOGY).
Renal Impairment:
). Monitor subjects treated with ONDEXXYA for signs and symptoms of arterial and venous thromboembolic events, ischemic events, and cardiac arrest. To reduce thromboembolic risk, resume anticoagulant therapy as soon as medically appropriate following treatment with ONDEXXYA.
The safety of ONDEXXYA has not been evaluated in subjects who experienced thromboembolic events or disseminated intravascular coagulation within two weeks prior to the life-threatening bleeding event requiring treatment with ONDEXXYA.
Safety of ONDEXXYA also has not been evaluated in subjects who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within seven days prior to the bleeding event. Time Course of Reversal of Anti-FXa Activity The time course of anti-FXa activity following ONDEXXYA administration was consistent among the healthy volunteer studies and the ANNEXA-4 study in bleeding subjects.
Compared to baseline, there was a rapid and substantial decrease in anti-FXa activity corresponding to the ONDEXXYA bolus. This decrease was sustained through the end of the ONDEXXYA continuous infusion. The anti-FXa activity returned to the placebo levels approximately two hours after completion of a bolus or continuous infusion.
Subsequently, the anti-FXa activity decreased at a rate similar to the clearance of the FXa inhibitors. A total of 128 patients from ANNEXA-4 were anticoagulated and had elevated baseline levels of anti-FXa (>150 ng/mL for apixaban, >300 ng/mL for rivaroxaban).
After administration of Tris base (tromethamine) Tris hydrochloride ONDEXXYA® (andexanet alfa) Page 10 of 32 ONDEXXYA, these patients experienced decreased anti-FXa activity levels, with median reductions of 96% for rivaroxaban and 92% for apixaban.
, thromboembolic events). Treatment monitoring of ONDEXXYA should not be based on anti-FXa activity. Commercial anti-FXa activity assays are unsuitable for measuring anti-FXa activity following administration of ONDEXXYA as these assays result in erroneously elevated anti-FXa activity levels, thereby causing a substantial underestimation of the reversal activity of ONDEXXYA.
, Hematologic). 1 Dosing Considerations For intravenous (IV) use only. Patients being treated with FXa inhibitors 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 (see 7 WARNINGS AND PRECAUTIONS, Hematologic). 2 Recommended Dose and Dosage Adjustment • Select the appropriate dosing regimen following the guidance in Table 1.
• Administer ONDEXXYA as an IV bolus followed by administration of a continuous infusion as per Table 2. The recommended dosing of ONDEXXYA is based on the specific FXa inhibitor, dose of FXa inhibitor, and time since the patient’s last dose of FXa inhibitor (see Table 1).
Table 1 - ONDEXXYA Dose Based on Rivaroxaban or Apixaban Dose and Timing of Last Dose of FXa Inhibitor before ONDEXXYA Initiation FXa Inhibitor FXa Inhibitor Last Dose < 8 Hours or Unknown ≥ 8 Hours Rivaroxaban ≤ 10 mg Low Dose Low Dose > 10 mg or Unknown High Dose Apixaban ≤ 5 mg Low Dose > 5 mg or Unknown High Dose The low- and high-dose regimens are described in Table 2.
Table 2 - ONDEXXYA dosing regimens Dose* Initial IV Bolus Follow-On IV Infusion** Total number of 200 mg vials Low Dose 400 mg at a target rate of 30 mg/min 4 mg/min for 120 minutes (480 mg) 5 (2 vials bolus + 3 vials infusion) High Dose 800 mg at a target rate of 30 mg/min 8 mg/min for 120 minutes (960 mg) 9 (4 vials bolus + 5 vials infusion) * The safety and efficacy of more than one dose have not been evaluated.
** Because the recommended infusion doses are lower than the andexanet alfa content of the vials, there will be a small amount of solution remaining in the bag after completion of the infusion. IV=intravenous infusion ONDEXXYA® (andexanet alfa) Page 6 of 32 Special Populations Pediatrics (< 18 years of age): Health Canada has not authorized an indication for pediatric use.
• ONDEXXYA is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
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The effect of renal impairment on ONDEXXYA exposure levels has not been evaluated. Because andexanet alfa is a protein and is given as a one-time treatment, no dose adjustment is recommended.
Hepatic Impairment:
The safety and efficacy of ONDEXXYA have not been studied in patients with hepatic impairment. Biliary and/or feces elimination of protein therapeutics is not a known route of protein elimination. Because andexanet alfa is a protein and is given as a one-time treatment, no dose adjustment is recommended.
3 Reconstitution ONDEXXYA 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. Two IV infusion bags will be prepared to deliver the selected ONDEXXYA regimen.
One bag containing the bolus dose and one bag containing the follow-on IV infusion. The reconstituted solution contains andexanet alfa at a concentration of 10 mg/mL. Chemical and physical in-use stability has been demonstrated over a 24-hour period.
The reconstituted solution in the primary packaging vials can be stored for 16 hours at 2°C to 8°C. If necessary, the reconstituted solution can be stored at room temperature for an additional eight hours after being transferred to the IV bag.
To minimize the risk of microbial growth, once reconstituted, it is recommended that the product be used immediately. ONDEXXYA® (andexanet alfa) Page 7 of 32 IV Bolus Preparation Determine total number of vials required (see Table 2).
200 mg vials: Reconstitute the 200 mg vial of ONDEXXYA with 20 mL of Sterile Water for Injection (SWFI). Use a 20-mL (or larger) syringe and 20-gauge (or higher) needle. Slowly inject the SWFI, directing the solution onto the inside wall of the vial to minimize foaming.
To reduce the total reconstitution time needed during preparation, reconstitute all required vials in succession. To ensure dissolution of the cake or powder, gently swirl each vial until complete dissolution of powder occurs (A). Do not shake (B); shaking could lead to foaming.
Typical dissolution time for each vial is approximately three to five minutes. If dissolution is incomplete, discard the vial, and do not use the product. Upon reconstitution, the parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration.
(A) (B) Use 60-mL (or larger) syringe with a 20-gauge (or higher) needle to withdraw the reconstituted ONDEXXYA solution from each of the vials until the required dosing volume is achieved. Note the total volume withdrawn into the syringe.
Transfer the ONDEXXYA solution from the syringe into an empty polyolefin or polyvinyl chloride IV bag with a volume of 250 mL or less. ONDEXXYA® (andexanet alfa) Page 8 of 32 Discard the syringe, needle and vials (including any unused product) in accordance with local requirements.
Continuous IV Infusion Preparation Follow the same procedure outlined above for IV bolus preparation. Reconstitute the total number of vials needed based on the dose requirements (see Table 2). More than one 40 to 60 mL syringe, or an equivalent 100-mL syringe, may be used for transfer of reconstituted solution to the IV bag.
Discard the syringe, needle and vials (including any unused product) in accordance with local requirements. 4 Administration Upon reconstitution, the parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration.
22 micron in-line polyethersulfone or equivalent low protein-binding filter. Start the bolus at a target rate of approximately 30 mg/min. Within two minutes following the bolus dose, administer the continuous IV infusion for up to 120 minutes.
5 Missed […]
ONDEXXYA Use in Conjunction with Other Supportive Measures ONDEXXYA can be used in conjunction with standard hemostatic 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.
, 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 ONDEXXYA may interfere with the anticoagulant effect of heparin. Use of ONDEXXYA as an antidote for heparin has not been evaluated and is not recommended. Avoid use of ONDEXXYA for the reversal of FXa inhibitors (apixaban and rivaroxaban) prior to heparinization as ONDEXXYA may cause unresponsiveness to heparin.
If anticoagulation is needed, use an alternative anticoagulant to heparin. Infusion-related reactions In case of mild or moderate infusion reactions, careful observation may be sufficient. For moderate symptoms, a brief interruption or slowing of the infusion with resumption of the infusion after symptoms subside may be considered.
Based on clinical judgement, appropriate medical treatment may be administered. Immune As with all therapeutic proteins, there is the potential for immunogenicity (see 8 ADVERSE REACTIONS). 1 Pregnant Women There are insufficient data on the use of ONDEXXYA in pregnant women to determine if ONDEXXYA exposure during pregnancy poses any risk to the mother or fetus.
Animal ONDEXXYA® (andexanet alfa) Page 11 of 32 reproductive and developmental studies have not been conducted with ONDEXXYA. ONDEXXYA is not recommended during pregnancy. 2 Breast-feeding It is unknown if ONDEXXYA is excreted in human milk.
Precaution should be exercised because many drugs can be excreted in human milk. A risk to breastfed newborns/infants cannot be excluded. 3 Pharmacokinetics. 3 Pediatrics Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
4 Geriatrics Geriatrics (≥ 65 years of age): Of the 477 subjects in the ANNEXA-4 study of ONDEXXYA, 431 (90%) were 65 years of age or older, and 315 (66%) were older than 75 years of age. No overall differences in safety or efficacy were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between elderly and younger patients.
1 Adverse Reaction Overview The safety of ONDEXXYA has been evaluated in clinical trials including 417 healthy subjects administered a FXa inhibitor, as well as in 477 patients in a Phase 3b/4 study (ANNEXA-4), who had acute major bleeding and were under treatment with a FXa inhibitor (mostly apixaban or rivaroxaban).
Healthy Volunteer Pooled Analysis A total of 417 healthy subjects were included in the pooled ONDEXXYA (all doses) analysis set and 156 subjects were included in the pooled placebo analysis set. Of the 417 healthy subjects, 143 received only bolus doses (ranging from 90 mg to 800 mg) and 274 received bolus doses (ranging from 400 to 800 mg) followed by continuous infusion of 4 mg/min (low dose) or 8 mg/min (high dose) for 120 minutes (ranging from 480 to 960 […]
Geriatrics (≥ 65 years of age):
No dose adjustment is recommended for elderly patients (≥ 65 years of age) (see 7 WARNINGS AND PRECAUTIONS and 10 CLINICAL PHARMACOLOGY).
Renal Impairment:
The effect of renal impairment on ONDEXXYA exposure levels has not been evaluated. Because andexanet alfa is a protein and is given as a one-time treatment, no dose adjustment is recommended.
Hepatic Impairment:
The safety and efficacy of ONDEXXYA have not been studied in patients with hepatic impairment. Biliary and/or feces elimination of protein therapeutics is not a known route of protein elimination. Because andexanet alfa is a protein and is given as a one-time treatment, no dose adjustment is recommended.
3 Reconstitution ONDEXXYA 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. Two IV infusion bags will be prepared to deliver the selected ONDEXXYA regimen.
One bag containing the bolus dose and one bag containing the follow-on IV infusion. The reconstituted solution contains andexanet alfa at a concentration of 10 mg/mL. Chemical and physical in-use stability has been demonstrated over a 24-hour period.
The reconstituted solution in the primary packaging vials can be stored for 16 hours at 2°C to 8°C. If necessary, the reconstituted solution can be stored at room temperature for an additional eight hours after being transferred to the IV bag.
To minimize the risk of microbial growth, once reconstituted, it is recommended that the product be used immediately. ONDEXXYA® (andexanet alfa) Page 7 of 32 IV Bolus Preparation Determine total number of vials required (see Table 2).
200 mg vials: Reconstitute the 200 mg vial of ONDEXXYA with 20 mL of Sterile Water for Injection (SWFI). Use a 20-mL (or larger) syringe and 20-gauge (or higher) needle. Slowly inject the SWFI, directing the solution onto the inside wall of the vial to minimize foaming.
To reduce the total reconstitution time needed during preparation, reconstitute all required vials in succession. To ensure dissolution of the cake or powder, gently swirl each vial until complete dissolution of powder occurs (A). Do not shake (B); shaking could lead to foaming.
Typical dissolution time for each vial is approximately three to five minutes. If dissolution is incomplete, discard the vial, and do not use the product. Upon reconstitution, the parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration.
(A) (B) Use 60-mL (or larger) syringe with a 20-gauge (or higher) needle to withdraw the reconstituted ONDEXXYA solution from each of the vials until the required dosing volume is achieved. Note the total volume withdrawn into the syringe.
Transfer the ONDEXXYA solution from the syringe into an empty polyolefin or polyvinyl chloride IV bag with a volume of 250 mL or less. ONDEXXYA® (andexanet alfa) Page 8 of 32 Discard the syringe, needle and vials (including any unused product) in accordance with local requirements.
Continuous IV Infusion Preparation Follow the same procedure outlined above for IV bolus preparation. Reconstitute the total number of vials needed based on the dose requirements (see Table 2). More than one 40 to 60 mL syringe, or an equivalent 100-mL syringe, may be used for transfer of reconstituted solution to the IV bag.
Discard the syringe, needle and vials (including any unused product) in accordance with local requirements. 4 Administration Upon reconstitution, the parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration.
22 micron in-line polyethersulfone or equivalent low protein-binding filter. Start the bolus at a target rate of approximately 30 mg/min. Within two minutes following the […]