Coagulation Factor Xa (Recombinant), Inactivated-Zhzo - Uses, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Overview

Coagulation factor Xa (recombinant), inactivated-zhzo, is a new medication that significantly improves the treatment of bleeding problems. It is indicated for the supplementation of efficient blood clotting, and this recombinant drug was recently approved by the U.S. FDA (United States Food and Drug Administration) on May 3, 2018. By targeting and inhibiting factor Xa at the site where blood coagulation normally occurs in the coagulation cascade, inactivated-zhzo provides a safe and controlled manner by which to manage excess bleeding and indeed offers greater, improved safety and efficacy to offer to patients who need anticoagulation reversal.

Drug Group

Coagulation factor Xa (recombinant), inactivated-zhzo, is classified in a medicine group called anticoagulant reversal agents. Coagulation factor Xa is used specifically to overturn the anticoagulant activity of Rivaroxaban and Apixaban (both factor Xa inhibitors). The drug binds with anticoagulants, effectively neutralizing them and restoring the clotting ability in life-threatening or uncontrolled bleeding.

Indications

• Coagulation factor Xa (recombinant), inactivated-zhzo, is approved for use in patients treated with Rivaroxaban or Apixaban when there is a need to reverse anticoagulation due to life-threatening or uncontrolled bleeding.

• This approval was granted under an accelerated process based on changes in anti-FXa (anti-factor Xa) activity observed in healthy volunteers. However, efficacy in improving hemostasis (a mechanism that controls bleeding) has yet to be demonstrated.

• Approval may continue depending on the outcomes of future studies that demonstrate improvement in patient hemostasis.

Limitations of Use: Coagulation factor Xa (recombinant), inactivated-zhzo, is not indicated for and has not been proven effective in treating bleeding related to FXa inhibitors other than Apixaban or Rivaroxaban.

Dosage Forms and Available Strengths

Coagulation factor Xa (recombinant), inactivated-zhzo is an off-white or white lyophilized powder in single-use vials; each vial contains 200 mg (milligrams) coagulation factor Xa (recombinant), inactivated-zhzo.

Black Box Warning

There are serious and life-threatening adverse effects associated with the treatment, as follows:

• Thromboembolic Events: These are conditions in which a blood clot forms in one region of the body and then travels through the blood vessels to different areas, causing blockages. Both arterial and venous events are experienced.

• Ischemic Events: It include myocardial infarction, which interrupts the blood supply to a portion of the heart muscle, and ischemic stroke, which occurs when a blood clot prevents blood flow to a portion of the brain.

• Cardiac Arrest: A sudden loss of cardiac function, resulting in the inability of the heart to pump blood effectively.

• Sudden Deaths: These are unforeseen deaths that can result from serious complications of the treatment itself or the underlying disorders.

Monitoring for thromboembolic events (when a clot travels and blocks the blood vessel) is essential, and anticoagulation should be initiated when appropriate. Symptoms indicating potential cardiac arrest should also be closely observed, and treatment should be administered as needed.

For Patients

How Does the Coagulation Factor Xa (Recombinant), Inactivated-Zhzo Work in Hemophilia A?

Hemophilia A is a genetic disorder that causes rare bleeding due to a deficiency or defect of clotting factor VIII, an important protein for blood coagulation. The hallmark of hemophilia A is prolonged or spontaneous bleeding, particularly into joints and muscles. This may cause damage to the joints and lead to a series of complications. It is usually inherited and almost always affects men, although women can be carriers. The treatment involves replacing the missing factor VIII to manage and prevent bleeding episodes. Coagulation factor Xa (recombinant), inactivated-zhzo, reverses the effects of certain anticoagulants, specifically factor Xa inhibitors like Apixaban and Rivaroxaban. These anticoagulants block the activity of factor Xa, a crucial enzyme in blood clotting. The drug is designed to counteract this by providing a modified form of factor Xa that binds to the inhibitors, neutralizing their anticoagulant effects. This helps restore the blood’s ability to clot, which is crucial in situations where rapid reversal of anticoagulation is needed, such as in cases of major bleeding or before urgent surgical procedures.

How Is Coagulation Factor Xa (Recombinant), Inactivated-Zhzo Administered?

Coagulation factor Xa (recombinant), inactivated-Zhzo, is administered in a clinical setting and is given intravenously or into the vein (IV).

The administration involves two steps:

• IV Bolus: Start with an initial bolus dose at a target rate of 30 mg per minute.

• Continuous IV Infusion: Within two minutes after the bolus, continue with an IV infusion for 120 minutes. The infusion requires a 0.2 or 0.22-micron in-line polyethersulfone or equivalent low protein-binding filter.

Dosing depends on the specific FXa inhibitor, its dose, and the time since the last dose. Before being administered, the reconstituted solution should be visually checked for particles and discoloration.

What Are the Side Effects of Coagulation Factor Xa (Recombinant), Inactivated-Zhzo?

Common side effects of coagulation factor Xa (recombinant), inactivated-zhzo:

• Urinary tract infections (more than five percent).

• Pneumonia (more than or equal to five percent) is a lung infection that causes cough, fever, and difficulty breathing.

Clinical Trials Observations:

1. Deaths (18 percent of subjects):

• Cardiovascular deaths related to bleeding.

• Cardiovascular deaths are not associated with bleeding.

2. Non-cardiovascular deaths.

• Deaths of uncertain or unknown cause.

3. Thromboembolic and ischemic events (10 percent of subjects). It includes:

• Cerebrovascular Accident (CVA): It is a stroke from a blocked or burst brain blood vessel.

• Deep Venous Thrombosis (DVT): Blood clot in a deep vein, often in the legs.

• Myocardial Infarction (Heart Attack).

• Pulmonary Embolism: Blockage in lung blood vessels, usually from a blood clot.

• Transient Ischemic Attack (TIA): Temporary blockage of brain blood flow or mini-stroke.

4. Infusion-related reactions (0.5 percent of subjects):

• Rigors.

• Chills.

• Hypertension (high blood pressure).

• Oxygen desaturation.

• Agitation (restlessness).

• Confusion.

What Are the Things to Inform the Doctor Before Taking Coagulation Factor Xa (Recombinant), Inactivated-Zhzo?

The following should be informed to the doctor before taking Coagulation factor Xa, recombinant, inactivated-zhzo:

• Allergies: Any known allergies, particularly to medications or components of the product.

• Medical History: Any history of blood clotting disorders, liver or kidney issues, or other significant health conditions.

• Current Medications: All medications currently being taken, including over-the-counter (OTC) drugs, supplements, and herbal products.

• Recent or Planned Surgery: Any recent or upcoming surgeries or procedures, including dental work.

• Pregnancy or Breastfeeding: If there is a chance of pregnancy, planning to become pregnant, or breastfeeding.

• Bleeding Risks: Any history of bleeding disorders or recent incidents of abnormal bleeding or bruising.

Dietary Considerations

No special considerations are required unless directed by the doctor.

Missed Dose

Coagulation factor Xa (recombinant), inactivated-zhzo is administered in a clinical setting; therefore, missing a dose is not possible. If a dose is missed, give it as soon as possible. If the next dose is approaching, do not take the missed dose. Just resume the normal dosing schedule. Avoid doubling the dose to catch up.

Overdose

If there is an overdose, get medical assistance or contact a poison control center immediately.

Storage and Handling

Coagulation factor Xa, inactivated-zhzo, comes as a white to off-white powder in single-use vials packaged in cartons. It is available in two configurations: one with four vials, each containing 200 mg of Coagulation Factor Xa, inactivated-Zhao, and another with five vials of the same dosage. The vials have red flip-off caps, and the carton packaging features a red-to-blue stripe and a blue "200 mg per vial" label. Coagulation factor Xa, inactivated-zhzo, is not made with natural rubber latex. Store unopened vials in the refrigerator at two°C or degrees Celsius to eight°C (36 to 46°F or degrees Fahrenheit) and do not freeze.

For Doctors

Description:

Coagulation factor Xa (recombinant), inactivated-zhzo, is a sterile lyophilized powder, white to off-white, provided in single-use vials, each containing 200 mg of factor Xa. It is formulated with tromethamine, Tris hydrochloride, L-arginine hydrochloride, sucrose, mannitol, and polysorbate 80 at pH (potential of hydrogen) 7.8.

Reconstituted with sterile water, it forms a clear to slightly yellow solution. Coagulation factor Xa (recombinant), inactivated-zhzo contains no preservatives. It is a genetically modified variant of human factor Xa, designed to prevent anticoagulant effects by altering its active site and removing the Gla domain. It is produced in CHO cells and includes two validated virus clearance steps.

Warnings and Precautions

• Thromboembolic and Ischemic Risks: In the Coagulation factor Xa (recombinant), inactivated-zhzo-4 study, 10.7 percent of 419 patients treated with Coagulation factor Xa (recombinant), inactivated-zhzo after Apixaban or Rivaroxaban had a blood clot. Of those who resumed anticoagulants, 5.3 percent had a clot after restarting. Monitor for blood clots and restart anticoagulants as soon as safe.

• Re-elevation or Incomplete Reversal: Coagulation factor Xa (recombinant), inactivated-zhzo quickly lowers anti-FXa activity, which returns to normal about two hours after treatment. In the study, anti-FXa activity decreased by 96 percent for Rivaroxaban and 92 percent for Apixaban.

• Use of Heparin: Coagulation factor Xa (recombinant), inactivated-zhzo may affect Heparin’s effectiveness. Avoid using the drug before Heparin and consider alternative anticoagulants if needed.

What Are the Pharmacological Actions of Metoclopramide Nasal Spray?

Mechanism of Action: Coagulation factor Xa (recombinant), inactivated-zhzo, promotes coagulation by binding to and sequestering FXa inhibitors such as Rivaroxaban and Apixaban. Additionally, the drug inhibits the activity of tissue factor pathway inhibitor (TFPI), which can enhance tissue factor (TF)-initiated thrombin generation.

Pharmacodynamics: The effects of Coagulation factor Xa (recombinant), inactivated-zhzo can be evaluated by measuring its impact on anti-FXa activity, the free fraction of FXa inhibitors, and thrombin generation. The drug binds to Rivaroxaban and Apixaban and inhibits TFPI activity.

In studies, Coagulation factor Xa (recombinant), inactivated-zhzo, was given as a bolus followed by a continuous two-hour infusion. This regimen quickly reduced anti-FXa activity within two minutes of the bolus and maintained lower levels throughout the infusion. Anti-FXa activity returned to baseline about two hours after treatment, while TFPI levels returned to normal after about 96 hours.

Thrombin generation increased above baseline within two minutes of bolus administration and stayed elevated for at least 22 hours. This increase in thrombin generation was not seen in assays unaffected by TF-TFPI interaction. Commercial anti-FXa assays may not accurately measure FXa activity after the drug administration due to its reversible binding with FXa inhibitors, leading to a potential underestimation of its reversal effect.

Pharmacokinetics

Coagulation factor Xa (recombinant), inactivated-zhzo's pharmacokinetic properties in healthy subjects show that for low doses, the area under the curve (AUC) is 200.5 hrµg/mL (hour-microgram per milliliter), with a peak concentration (Cmax) of 76.6 µg/mL (micrograms per milliliter), a clearance rate of 4.4 L/hr (liters per hour), a half-life (T1/2) of 3.3 hours, and a volume of distribution at steady state (Vss) of 4.4 liters. For high doses, these values increase to 572.9 hrµg/mL or hour-micrograms per milliliter for AUC, 206.6 µg/mL for Cmax, 3.1 L/hr for clearance, 2.7 hours for T1/2 (half shell life), and 3.0 liters for Vss (volume of distribution at steady state).

The pharmacokinetics of Coagulation Factor Xa (recombinant) inactivated-zhzo are not influenced by Apixaban or Rivaroxaban. Immunogenicity studies reveal that among 417 healthy subjects, up to 8.7 percent had anti-coagulation factor Xa (recombinant), inactivated-zhzo antibodies, and 0.8 percent had anti-FXa antibodies, with no anti-FX antibodies detected. Similarly, in the study involving 277 patients with major bleeding, 7.9 percent had anti-coagulation factor Xa (recombinant), inactivated-zhzo antibodies, 0.4 percent had anti-FXa antibodies, and no anti-FX antibodies were observed. Neither study detected neutralizing antibodies.

Non-Clinical Toxicity:

No animal studies were conducted to assess Coagulation factor Xa (recombinant), inactivated-zhzo's effects on cancer development, genetic mutations, or reproductive fertility.

What Are the Contraindications of Coagulation Factor Xa (Recombinant), Inactivated-Zhzo?

There are no contraindications.

What Are the Drug Interactions of Coagulation Factor Xa (Recombinant), Inactivated-Zhzo?

Coagulation factor Xa (Recombinant), inactivated-zhzo, has no known significant drug interactions.

Clinical Studies

Coagulation factor Xa (recombinant), inactivated-zhzo's safety and efficacy were tested in three studies. Studies 1 and 2 involved healthy volunteers and compared the drug to placebo in reversing Apixaban and Rivaroxaban, respectively. In both studies, Coagulation factor Xa (recombinant), inactivated-zhzo significantly reduced anti-FXa activity compared to placebo. Study 3 looked at the drug in patients with major bleeding who were on FXa inhibitors. This study found a significant decrease in anti-FXa activity but did not establish improvement in bleeding control. Coagulation factor Xa (recombinant), inactivated-zhzo's, has not been proven effective for FXa inhibitors other than Apixaban and Rivaroxaban.

Use in Specific Populations

• Pregnancy: Use of this drug in pregnancy has not been studied; not enough evidence exists on the possible risks and benefits.

• Labor and Delivery: No formal studies have been conducted on the Coagulation factor Xa (recombinant), inactivated-zhzo, for use during labor and delivery.

• Lactation: It is unknown whether Coagulation factor Xa (recombinant), inactivated-zhzo, is discharged into breast milk or poses a risk to a breastfeeding baby. Take into account the advantages of breastfeeding for both the baby's growth and well-being, in addition to the mother's medical necessity for Coagulation factor Xa (recombinant), inactivated-zhzo, and any potential adverse effects on the breastfed child from Coagulation factor Xa (recombinant), inactivated-zhzo, or from the underlying maternal condition.

• Pediatric Use: Safety and efficacy have not been proven in children. Coagulation factor Xa (recombinant), inactivated-zhzo, has not been studied in children, so its safety and effectiveness in this group are unknown.

• Geriatric Patients: Controlled clinical studies of Coagulation factor Xa (recombinant), inactivated-zhzo included 182 subjects who were 65 years of age and over. There were no differences in safety or effectiveness observed between these subjects and those younger than 65 years of age, and other clinical reports have not found variations in reactions between older and younger subjects, although heightened sensitivity in some elderly individuals cannot be dismissed.