ANDEXXA

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# Black Box Warning

# Overview
ANDEXXA is a Factor Xa reversal agent that is FDA approved for the {{{indicationType}}} of ANDEXXA, coagulation factor Xa (recombinant), inactivated-zhzo is a recombinant modified human Factor Xa (FXa) protein indicated for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include urinary tract infections, pneumonia, infusion-related reactions.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- There are two dosing regimens:
- Low Dose: 400 mg at a target rate of 30 mg/min; Follow-On IV infusion: 4 mg/min for up to 120 minutes
- High Dose: 800 mg at a target rate of 30 mg/min; Follow-On IV infusion: 8 mg/min for up to 120 minutes
- Dosing Information
- For Rivaroxaban  10 mg, give low dose ANDEXXA if the timing of FXa inhibitor last dose before ANDEXXA initiation is < 8 hours, unknown or  8 hours
- For Rivaroxaban > 10 mg / Unknown high dose, give high dose ANDEXXA if the timing of FXa inhibitor last dose before ANDEXXA initiation is < 8 hours or unknown and give low dose ANDEXXA if the timing of FXa inhibitor last dose before ANDEXXA initiation is  8 Hours
- For Apixaban  5 mg, give low dose ANDEXXA if the timing of FXa inhibitor last dose before ANDEXXA initiation is < 8 hours, unknown or  8 hours
- For Apixaban > 5 mg / Unknown high dose, give high dose ANDEXXA if the timing of FXa inhibitor last dose before ANDEXXA initiation is < 8 hours or unknown and give low dose ANDEXXA if the timing of FXa inhibitor last dose before ANDEXXA initiation is  8 Hours

## Off-Label Use and Dosage (Adult)

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The safety and efficacy of ANDEXXA in the pediatric population have not been studied.

## Off-Label Use and Dosage (Pediatric)

# Contraindications
There are no contraindications to the use of ANDEXXA.

# Warnings
- 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.
- 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.
- 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.
- 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 antiFXa activity decreased at a rate similar to the clearance of the FXa inhibitors.
- Thirty-eight patients who were anticoagulated with apixiban 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.

# Adverse Reactions

## 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 occured 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.
In 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%)
- 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.
- Pneumonia

## Postmarketing Experience
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# Drug Interactions
- Drug 1
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- Drug 5
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# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
There 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.
Pregnancy Category (AUS): 
(Description)

### Labor and Delivery
The safety and effectiveness of ANDEXXA during labor and delivery have not been evaluated.

### Nursing Mothers
There 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 mothers clinical need for ANDEXXA and any potential adverse effects on the breastfed child from ANDEXXA or from the underlying maternal condition.

### Pediatric Use
The safety and efficacy of ANDEXXA in the pediatric population have not been studied.

### Geriatic 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.

### Gender
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### Race
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### Renal Impairment
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### Hepatic Impairment
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### Females of Reproductive Potential and Males
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### Immunocompromised Patients
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### Others
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# Administration and Monitoring

### Administration
(Oral/Intravenous/etc)

### Monitoring
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)

# IV Compatibility
There is limited information regarding the compatibility of ANDEXXA and IV administrations.

# Overdosage

## Acute Overdose

### Signs and Symptoms
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### Management
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## Chronic Overdose

### Signs and Symptoms
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### Management
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# Pharmacology

## 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.

## Structure
(Description with picture)

## Pharmacodynamics
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  10 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.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 TFTFPI interaction).

## Pharmacokinetics
Distribution
The volume of distribution (Vd) for ANDEXXA is approximately equivalent to the blood
volume of 5 L.
Elimination
Clearance for ANDEXXA is approximately 4.3 L/hr. The elimination half-life ranges from 5 to
7 hours.
Drug-Drug Interaction
The 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).

## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal studies were performed to evaluate the effects of ANDEXXA on carcinogenesis, mutagenesis, or impairment of fertility.

# Clinical Studies
The safety and efficacy of ANDEXXA were evaluated in two prospective, randomized, placebocontrolled 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.
Study 1(NCT02207725)  apixaban reversal
In 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 reversal
In 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 Activity
The 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.
(Description)

# How Supplied
How Supplied
- ANDEXXA 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.

## Storage
There is limited information regarding ANDEXXA Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# 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.

# Precautions with Alcohol
Alcohol-ANDEXXA interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
There is limited information regarding ANDEXXA Brand Names in the drug label.

# Look-Alike Drug Names
- (Paired Confused Name 1a)  (Paired Confused Name 1b)
- (Paired Confused Name 2a)  (Paired Confused Name 2b)
- (Paired Confused Name 3a)  (Paired Confused Name 3b)

# Drug Shortage Status
Drug Shortage

# Price