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Warning: Thromboembolic Risks, Ischemic Risks, Cardiac Arrest, And Sudden Deaths
- Treatment with ANDEXXA has been associated with serious and life-threatening adverse events, including: (5.1)Arterial and venous thromboembolic events Ischemic events, including myocardial infarction and ischemic stroke Cardiac arrest Sudden deathsMonitor for thromboembolic events and initiate anticoagulation when medically appropriate. Monitor for symptoms and signs that precede cardiac arrest and provide treatment as needed.
1 Indications And Usage
ANDEXXA is indicated for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.This indication is approved under accelerated approval based on the change from baseline in anti-FXa activity in healthy volunteers [see Clinical Studies (14)]. An improvement in hemostasis has not been established. Continued approval for this indication may be contingent upon the results of studies to demonstrate an improvement in hemostasis in patients.
Limitation of UseANDEXXA has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any FXa inhibitors other than apixaban and rivaroxaban.
- IV Bolus PreparationReconstitute each 100 mg vial of ANDEXXA (Figure A) using a 10-mL syringe and 20-gauge (or higher) needle. Slowly inject 10 mL Sterile Water for Injection (SWFI), USP, directing the solution onto the inside wall of the vial to minimize foaming (Figure A). (Figure A)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. Do not shake; shaking could lead to foaming (Figure B). Typical dissolution time for each vial is approximately 3 to 5 minutes. If dissolution is incomplete, discard the vial and do not use the product. (Figure B)Use 60-mL or larger syringe with a 20-gauge (or higher) needle to withdraw the reconstituted ANDEXXA solution from each of the vials until the required dosing volume is achieved. Note the total volume withdrawn into the syringe.Transfer the ANDEXXA solution from the syringe into an empty polyolefin or polyvinyl chloride IV bag with a volume of 250 mL or less (Figure C). (Figure C)Discard the syringe and needle.Discard the vials, including any unused portion.
- Continuous IV Infusion PreparationFollow the same procedure outlined above for IV bolus preparation. Reconstitute the number of vials needed based on the dose requirements. 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. Infusion will require a 0.2 or 0.22 micron in-line polyethersulfone or equivalent low protein-binding filter.
DeathsIn the ongoing ANNEXA-4 study, there were 25 deaths (14%) prior to the Day 30 follow-up visit. Eight patients died within 10 days after the ANDEXXA infusion. The percentage of patients, by bleeding type, who died prior to the Day 30 follow-up visit was: 14% for intracranial bleeding, 10% for gastrointestinal bleeding, and 19% for other bleeding types.
Thromboembolic EventsIn the ongoing ANNEXA-4 study, 33/185 (17.8%) patients experienced one or more of the following events: deep venous thrombosis (11/33; 33%), ischemic stroke (9/33; 24%), acute myocardial infarction (5/33; 15%), pulmonary embolism (5/33; 15%), cardiogenic shock (3/33; 9%), sudden death (2/33; 6%), congestive heart failure (2/33; 6%), acute respiratory failure (2/33; 6%), cardiac arrest (1/33; 3%), cardiac thrombus (1/33; 3%), embolic stroke (1/33; 3%), iliac artery thrombosis (1/33; 3%), and non-sustained ventricular tachycardia (1/33; 3%). The median time to the first event in these 33 subjects was 6 days. Eleven of 33 (33%) patients were on antithrombotic therapy at the time of the event. [see Warnings and Precautions (5.1)]. No thromboembolic events were observed in 223 healthy volunteers who received FXa inhibitors and were treated with ANDEXXA.
Infusion-related ReactionsInfusion-related reactions occurred in 18% (39/223) of ANDEXXA-treated healthy volunteers vs. 6% (6/94) of placebo-treated subjects. These reactions were characterized by a range of symptoms including flushing, feeling hot, cough, dysgeusia, and dyspnea. Symptoms were mild to moderate in severity, and 90% (35/39) did not require treatment. One subject with a history of hives prematurely discontinued ANDEXXA after developing mild hives.
Risk SummaryThere are no adequate and well-controlled studies of ANDEXXA in pregnant women to inform patients of associated risks. Animal reproductive and development studies have not been conducted with ANDEXXA. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Labor or DeliveryThe safety and effectiveness of ANDEXXA during labor and delivery have not been evaluated.
Risk SummaryThere is no information regarding the presence of ANDEXXA in human milk, the effects on the breastfed child, or the effects on milk production.The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ANDEXXA and any potential adverse effects on the breastfed child from ANDEXXA or from the underlying maternal condition.
DistributionThe volume of distribution (Vd) for ANDEXXA is approximately equivalent to the blood volume of 5 L.
EliminationClearance for ANDEXXA is approximately 4.3 L/hr. The elimination half-life ranges from 5 to 7 hours.
Drug-Drug InteractionThe pharmacokinetics of ANDEXXA was not affected by apixaban (5 mg orally BID for 6 days) or rivaroxaban (20 mg orally once daily for 6 days).
Study 1(NCT02207725) – apixaban reversalIn Study 1, healthy subjects (median age: 57 years; range: 50 to 73 years) received apixaban 5 mg twice daily for 3.5 days to achieve steady-state. At 3 hours after the last apixaban dose (~ Cmax), ANDEXXA or placebo was administered. Eight subjects received placebo and 24 received ANDEXXA, administered as a 400 mg intravenous (IV) bolus followed by a 4 mg per minute continuous infusion for 120 minutes (total 480 mg).
Study 2 (NCT02220725) – rivaroxaban reversalIn Study 2, healthy subjects (median age: 57 years, range: 50 to 68 years) received rivaroxaban 20 mg once per day for 4 days to achieve steady-state. At 4 hours after the last rivaroxaban dose (~ Cmax), ANDEXXA or placebo was administered. Thirteen subjects received placebo and 26 received ANDEXXA, administered as an 800 mg IV bolus followed by an 8 mg per minute continuous infusion for 120 minutes (total 960 mg).
Reduction in Anti-FXa ActivityThe percent change from baseline in anti-FXa activity at its nadir was statistically significant (p < 0.0001) in favor of the ANDEXXA groups compared to placebo in both Studies 1 and 2. The results of Study 1 and Study 2 are provided in Table 3 (see below). The time courses of anti-FXa activity before and after ANDEXXA administration are shown in Figure 1.Table 3: Change in Anti-FXa ActivityAnti-FXa ActivityStudy 1(apixaban)Study 2(rivaroxaban)ANDEXXAn=23Placebon=8ANDEXXAn=26Placebon=13SD = Standard deviationNote: Baseline is the last assessment obtained prior to the first dose of ANDEXXA or placebo.Mean baseline ng/mL (± SD) 173.0(50.5)191.7(34.4)335.3(91.0)317.2(91.0)Mean ng/mL (± SD) change from baseline at the nadir Nadir is the smallest value for anti-FXa activity at the 110 minute (10 minutes prior to the end of the infusion) time point, 2-minute time point before completion of the infusion, or the 5 minute time point after the completion of the infusion for each subject.-160.6(49.3)-63.2(18.1)-324.5(89.2)-14.4(58.8)Mean % (± SD) change from baseline at the nadir -92.3(2.8)-32.7(5.6)-96.7(1.8)-44.6(11.8)95% Confidence interval (CI)The CI is for the Hodges-Lehman estimate of shift.-59.5 (-64.1, -55.2)-51.9 (-58.0, -47.0)p-value< 0.0001 p-value obtained from a 2-sided exact Wilcoxon rank-sum test.< 0.0001 Figure 1: Change in Anti-FXa Activity (ng/mL) in Subjects Anticoagulated with Apixaban (A – Study 1) and Rivaroxaban (B – Study 2)(A)(B)Anti-FXa activity was measured prior to and after ANDEXXA or placebo administration.Dashed lines indicate the end of the bolus or infusion. A break in the x-axis is added to better visualize the immediate, short-term dynamics of anti-FXa activity following ANDEXXA treatment. The points on the graph represent the mean anti-FXa activity level; error bars illustrate standard error. There was a statistically significant difference (p < 0.05) in the percent change of anti-FXa activity normalized to pre-bolus between ANDEXXA and placebo until 2 hours after administration of infusion.A. Apixaban – with ANDEXXA 400 mg IV bolus plus 4 mg/min infusion for 120 minutes.B. Rivaroxaban – with ANDEXXA 800 mg IV bolus plus 8 mg/min infusion for 120 minutes.
ANNEXA-4 (NCT02329327)In an ongoing multinational, prospective, single-arm, open-label study, ANDEXXA was administered to patients taking FXa inhibitors who presented with acute major bleeding.Interim results of the study include data for 185 patients. Of the 185 patients, 129 were considered efficacy-evaluable, defined as patients who: 1) were dosed with ANDEXXA; 2) had a baseline anti-FXa activity above 75 ng/mL; and 3) were adjudicated as meeting eligibility criteria for acute major bleeding. [also see Adverse Reactions (6)]. For anti-FXa activity, the median decrease from baseline to nadir was -93% for apixaban and -90% for rivaroxaban. ANDEXXA has not been shown to be effective for bleeding related to any FXa inhibitors other than apixaban and rivaroxaban.
How SuppliedANDEXXA is supplied in cartons of 4 single-use vials each containing 100 mg of ANDEXXA as a white to off-white lyophilized cake or powder.NDC 69853-0101-1
Portola Pharmaceuticals, Inc.South San Francisco, CA 94080 USAU.S. License No. 2017ADX-US-v1.3
2 Dosage And Administration
For intravenous use only.
There are two dosing regimens (see Table 1). The safety and efficacy of an additional dose has not been established.Table 1: ANDEXXA Dosing RegimensDoseThe safety and effectiveness of more than one dose have not been evaluated.Initial IV Bolus Follow-On IV InfusionLow Dose400 mg at a target rate of 30 mg/min4 mg/min for up to 120 minutesHigh Dose800 mg at a target rate of 30 mg/min8 mg/min for up to 120 minutesThe recommended dosing of ANDEXXA is based on the specific FXa inhibitor, dose of FXa inhibitor, and time since the patient's last dose of FXa inhibitor (see Table 2). Table 2: ANDEXXA Dose Based on Rivaroxaban or Apixaban DoseFXa InhibitorFXa Inhibitor Last DoseTiming of FXa Inhibitor Last Dose Before ANDEXXA Initiation< 8 Hours or Unknown≥ 8 HoursRivaroxaban≤ 10 mgLow Dose> 10 mg / UnknownHigh DoseLow DoseApixaban≤ 5 mgLow Dose> 5 mg / UnknownHigh Dose
- Upon reconstitution, the parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration.The reconstituted solution contains coagulation factor Xa (recombinant), inactivated-zhzo at a concentration of 10 mg/mL. Reconstituted ANDEXXA in vials is stable at room temperature for up to 8 hours, or may be stored for up to 24 hours at 2°C to 8°C.Reconstituted ANDEXXA in IV bags is stable at room temperature for up to 8 hours, or may be stored for up to 16 hours at 2°C to 8°C.
- Administer ANDEXXA intravenously, using a 0.2 or 0.22 micron in-line polyethersulfone or equivalent low protein-binding filter.Start the bolus at a target rate of approximately 30 mg/minute.Within 2 minutes following the bolus dose, administer the continuous IV infusion for up to 120 minutes.
2.4 Restarting Antithrombotic Therapy
Patients 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 the risk of thrombosis, resume anticoagulant therapy as soon as medically appropriate following treatment with ANDEXXA.
3 Dosage Forms And Strengths
ANDEXXA is available as a lyophilized powder in single-use vials of 100 mg of coagulation factor Xa (recombinant), inactivated-zhzo.
5.1 Thromboembolic And Ischemic Risks
Arterial and venous thromboembolic events, ischemic events, and cardiac events, including sudden death, were observed within 30 days post-ANDEXXA administration in 33 of the 185 patients (18%) evaluable for safety in the ongoing ANNEXA-4 study. The median time to first event was 6 days. Of the 86 patients who were re-anticoagulated prior to a thrombotic event, 11 (12.7%) patients experienced a thromboembolic, ischemic event, cardiac event or death. Monitor patients treated with ANDEXXA 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 ANDEXXA [see Dosage and Administration (2.4)]. The safety of ANDEXXA has not been evaluated in patients who experienced thromboembolic events or disseminated intravascular coagulation within two weeks prior to the life-threatening bleeding event requiring treatment with ANDEXXA. Safety of ANDEXXA also has not been evaluated in patients who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within seven days prior to the bleeding event.
5.2 Re-Elevation Or Incomplete Reversal Of Anti-Fxa Activity
The time course of anti-FXa activity following ANDEXXA administration was consistent among the healthy volunteer studies and the ANNEXA-4 study in bleeding patients [see Clinical Studies (14)]. Compared to baseline, there was a rapid and substantial decrease in anti-FXa activity corresponding to the ANDEXXA bolus. This decrease was sustained through the end of the ANDEXXA continuous infusion. Following the infusion, there was an increase in anti-FXa activity, which peaked 4 hours after infusion in ANNEXA-4 subjects. After this peak, the anti-FXa activity decreased at a rate similar to the clearance of the FXa inhibitors. Thirty-eight patients who were anticoagulated with apixaban had baseline levels of anti-FXa activity >150 ng/mL. Nineteen of these 38 (50%) patients experienced a > 93% decrease from baseline anti-FXa activity after administration of ANDEXXA. Eleven patients who were anticoagulated with rivaroxaban had baseline anti-FXa activity levels > 300 ng/mL. Five of the 11 patients experienced a > 90% decrease from baseline anti-FXa activity after administration of ANDEXXA.
6 Adverse Reactions
The most common adverse reactions (≥ 5%) in patients receiving ANDEXXA were urinary tract infections and pneumonia. The most common adverse reactions (≥ 3%) in healthy volunteers treated with ANDEXXA were infusion-related reactions.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.In the pooled safety analysis of clinical trials of ANDEXXA, 223 healthy volunteers received FXa inhibitors followed by treatment with ANDEXXA. The frequency of adverse reactions was similar in the ANDEXXA-treated group (120/223, 54%) and the placebo-treated group (54/94, 57%). Infusion-related adverse reactions occurred in 18% (39/223) of the ANDEXXA-treated group, and was the only adverse reaction that occurred more frequently than in the placebo group. No serious or severe adverse reactions were reported. The ANNEXA-4 study is an ongoing multinational, prospective, open-label study using ANDEXXA in patients presenting with acute major bleeding who have recently received a FXa inhibitor. To date, safety data are available for 185 patients. Approximately half of the patients are male with median age of 78 years. Patients had received either apixaban (98/185, 53%) or rivaroxaban (72/185, 40%), as anticoagulation treatment for atrial fibrillation (143/185, 77%) or venous thromboembolism (48/185, 26%). In the majority of patients, ANDEXXA was used to reverse anticoagulant therapy following either an intracranial hemorrhage (106; 57%) or a gastrointestinal bleed (58; 31%), with the remaining 21 patients (11%) experiencing bleeding at other sites. Patients were assessed at a 30-day follow-up visit following infusion of ANDEXXA.
As with all therapeutic proteins, there is the potential for immunogenicity. Using an electrochemiluminescence (ECL)-based assay, 145 ANDEXXA-treated healthy subjects were tested for antibodies to ANDEXXA as well as antibodies cross-reacting with Factor X (FX) and FXa. Low titers of anti-ANDEXXA antibodies were observed in 26/145 healthy subjects (17%); 6% (9/145) were first observed at Day 30 with 20 subjects (14%) still having titers at the last time point (Days 44 to 48). To date, the pattern of antibody response in patients in the ANNEXA-4 study has been similar to that observed in healthy volunteers with 6% (6/98) of the patients having antibodies against ANDEXXA. None of these anti-ANDEXXA antibodies were neutralizing. No antibodies cross-reacting with FX or FXa were detected in healthy subjects (0/145) or in bleeding patients (0/98) to date.Detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ANDEXXA with the incidence of antibodies to other products may be misleading.
8.4 Pediatric Use
The safety and efficacy of ANDEXXA in the pediatric population have not been studied.
8.5 Geriatric Use
Of the 185 subjects in the ANNEXA-4 study of ANDEXXA, 161 were 65 years of age or older and 113 were 75 years of age or older. No overall differences in safety or efficacy were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The pharmacokinetics of ANDEXXA in older (≥ 65 years, n=10) patients were not different compared to younger (18-45 years, n=10) patients.
ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) is a sterile, white to off-white lyophilized powder available in single-use vials, containing 100 mg of coagulation factor Xa formulated with the inactive ingredients tromethamine (Tris), L-arginine hydrochloride, sucrose (2% w/v), mannitol (5% w/v), and polysorbate 80 (0.01% w/v) at pH 7.8. After reconstitution of the lyophilized powder with sterile Water for Injection for intravenous (IV) administration, the product is a clear, colorless to slightly yellow solution. ANDEXXA contains no preservatives. The active ingredient in ANDEXXA is a genetically modified variant of human Factor Xa. The active site serine was substituted with alanine, rendering the molecule unable to cleave and activate prothrombin. The gamma-carboxyglutamic acid (Gla) domain was removed to eliminate the protein's ability to assemble into the prothrombinase complex, thus removing the potential anti-coagulant effects. No additives of human or animal origin are used in the manufacture of ANDEXXA. The recombinant protein is produced in a genetically engineered Chinese Hamster Ovary (CHO) cell expression system and has a molecular weight of approximately 41 kDa. The manufacturing process incorporates two validated virus clearance steps.
12.1 Mechanism Of Action
Coagulation factor Xa (recombinant), inactivated-zhzo exerts its procoagulant effect by binding and sequestering the FXa inhibitors, rivaroxaban and apixaban. Another observed procoagulant effect of the ANDEXXA protein is its ability to bind and inhibit the activity of Tissue Factor Pathway Inhibitor (TFPI). Inhibition of TFPI activity can increase tissue factor-initiated thrombin generation.
The effects of ANDEXXA can be measured using assays for its anti-FXa activity, free fraction of FXa inhibitor and thrombin generation. In addition to its ability to sequester the FXa inhibitors, rivaroxaban and apixaban, ANDEXXA has been shown to inhibit the Tissue Factor Pathway Inhibitor (TFPI) activity. The dose and dosing regimen of ANDEXXA that are required to reverse anti-FXa activity and to restore thrombin generation were determined in dose-ranging studies on healthy volunteers. Dosing of ANDEXXA, as a bolus followed by a 2-hour continuous infusion, resulted in a rapid decrease in anti-FXa activity (within two minutes after the completion of the bolus administration) followed by reduced anti-FXa activity that was maintained throughout the duration of the continuous infusion [see Clinical Studies (14)]. The anti-FXa activity returned to the placebo levels approximately 2 hours after completion of a bolus or continuous infusion. Whereas, TFPI activity in plasma was sustained for at least 22 hours following ANDEXXA administration.Elevation of Tissue Factor (TF)-initiated thrombin generation above the baseline range (prior to anticoagulation) occurred within two minutes following a bolus administration of ANDEXXA and was maintained throughout the duration of the continuous infusion. The TF-initiated thrombin generation was elevated above placebo for up to 22 hours. The sustained elevation of thrombin generation over the baseline range, and sustained elevation over placebo were not observed in a contact-activated thrombin generation assay (an assay that is not affected by TF-TFPI interaction).
13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
No animal studies were performed to evaluate the effects of ANDEXXA on carcinogenesis, mutagenesis, or impairment of fertility.
14 Clinical Studies
The safety and efficacy of ANDEXXA were evaluated in two prospective, randomized, placebo-controlled studies, conducted in healthy volunteers. Both studies examined the percent change in anti-FXa activity, from baseline to nadir, for the low-dose and high-dose regimens of bolus followed by continuous infusion. Nadir is defined as the smallest value measured within 5 minutes after the end of the continuous infusion.
Storage And Handling
Storage and HandlingUnopened vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE.
17 Patient Counseling Information
Inform patients that reversing FXa inhibitor therapy increases the risk of thromboembolic events. Arterial and venous thromboembolic events, ischemic events, cardiac events, and sudden death were observed within 30 days following ANDEXXA administration. [see Warnings and Precautions (5.1)].
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