Activated prothrombin complex concentrates made from human plasma, such as FEIBA and Autoplex, get around the Factor VIII inhibitor and restore thrombin.

Indications of activated Prothrombin complex concentrate (aPCC) derived from human plasma (factor eight inhibitor bypassing activity)

• Hemorrhage in patients with hemophilia:

  • When combined with inhibitors, it is used to regulate and stop bleeding episodes in people with haemophilia A and B.

• Perioperative bleeding management in patients with hemophilia:

  • It is recommended for the control of perioperative bleeding in individuals having inhibitors for haemophilia A and B.

• Routine prophylaxis of bleeding events in patients with hemophilia:

  • It can be administered prophylactically to people with haemophilia A and B who also take inhibitors to avoid or lessen their tendency to bleed.

• Off Label Use of aPCC in Adults:

  • haemophilia acquired with factor VIII or factor IX inhibitor titers greater than five Bethesda units (BU).
  • intracranial bleeding linked to anticoagulants other than vitamin K antagonists.
  • Associated with non-vitamin K antagonist anticoagulants is life-threatening bleeding

FEIBA/ Autoplex Dosage in adults:

Note: Human-derived anti-inhibitor coagulant complex mostly contains activated factor VII and non-activated therapeutic amounts of factors II, IX, and X.

FEIBA/ Autoplex Dose in the Control and prevention of bleeding episodes in patients with hemophilia:

Note: When the factor VIII inhibitor titer is greater than five Bethesda units (BU), it is given intravenously as the first line of treatment (antihemophilic factor may be recommended when titer is less than five BU).

• General dosing guidelines:

  • 50 to 100 units/kg/IV.
  • The location, intensity, and clinical condition of the bleeding all affect the dosage and length of the course of treatment.

• Joint hemorrhage:

  • 50 to 100 units/kg intravenously every 12 hours, or until the pain and acute impairments are under control.
  • 200 units/kg/day and 100 units/kg/dose are the maximum doses.

• Mucous membrane bleeding:

  • Every six hours for at least 24 hours, or until the bleeding stops, 50 to 100 units/kg intravenously.
  • 100 units/kg/dose and 200 units/kg/day are the maximum doses.

• Soft tissue hemorrhage (eg, retroperitoneal bleed):

  • until the bleed stops, 100 units/kg intravenously every 12 hours
  • 200 units/kg/day and 100 units/kg/dose are the maximum doses.

• Other severe hemorrhages (eg, intracranial hemorrhage):

  • Every six to twelve hours, 100 units/kg.
  • Continue until the bleeding stops.
  • 200 units/kg/day and 100 units/kg/dose are the maximum doses.

FEIBA/ Autoplex dose for Perioperative management:

• Preoperative:

  • 50 to 100 units/kg administered intravenously in a single dosage just prior to surgery.

• Postoperative:

  • every 6 to 12 hours until the bleeding stops and healing has taken place, 50 to 100 units/kg I/V.
  • 100 units/kg/dose and 200 units/kg/day are the maximum doses.

• Routine prophylaxis:

  • 85 units/kg intravenous every alternate day.

FEIBA/ Autoplex treatment dosage of moderate to severe Hemorrhage due to acquired hemophilia:

• Optimal dosing has not been established:

  • until bleeding stops, 50 to 100 units/kg every 8 to 12 hours.
  • Depending on the location, kind, and intensity of the bleeding, it can be sustained for 24 to 72 hours.
  • The daily dose cap is 200 units/kg.

FEIBA/ Autoplex dose of Intracranial hemorrhage associated with non-vitamin K antagonist anticoagulants:

• Oral direct factor Xa inhibitor-mediated (apixaban, edoxaban, rivaroxaban):

  • If intracranial haemorrhage occurred within 3 to 5 terminal half-lives of medication exposure or if concurrent hepatic failure existed, provide 50 units/kg I/V.

• Direct thrombin inhibitor-mediated (argatroban, dabigatran [if idarucizumab unavailable], bivalirudin, and desirudin):

  • If a direct thrombin inhibitor was administered within the preceding 3 to 5 half-lives and there is normal kidney function, or if there is renal impairment leading to drug exposure beyond the 3 to 5 half-lives, the dosage is 50 units/kg I/V.

• Pentasaccharide-mediated (fondaparinux):

  • 20 units/kg intravenous

Note: The NCS/SCCM guidelines advise avoiding reversal in patients receiving fondaparinux as a preventive dosage for venous thromboembolism unless there is proof of bioaccumulation or reduced clearance.

FEIBA/ Autoplex dose in Life-threatening bleeding associated with non-vitamin K antagonist anticoagulation:

• The ideal dosage has not been determined.
• A dosage range of 25 to 100 units/kg has been employed, which is based on numerous case reports involving different forms of bleeding caused by either dabigatran or rivaroxaban.
• In a research, an additional dose of 16 units/kg was given after 26 units/kg due to concerns about rebleeding.

Note: In comparison to nonactivated PCCs, anti-inhibitor coagulant complex (FEIBA, activated 4-factor PCC) may have a greater incidence of thrombosis, particularly at larger doses. Vein and arterial thrombosis must be closely monitored.

FEIBA/ Autoplex Dose in children:

Note:

• Based on the severity, location, type, and amount of inhibitors as well as a history of elevated antihemophilic inhibitor levels following use of antihemophilic factor preparations, the dose is represented in units of factor VIII inhibitor bypassing action.
• Only a bleed that poses a serious risk to life should be treated above the recommended dose. It is important to closely monitor for signs and symptoms of other thromboembolic events, disseminated intravascular coagulation, coronary ischemia, and/or other thromboembolic events.

FEIBA/ Autoplex Dose in the Control and prevention of bleeding episodes:

The dosage depends on the site and severity of bleeding.

• Joint hemorrhage:

  • until the pain is under control, provide intravenously 50 to 100 units/kg every 12 hours.
  • The daily dose cap is 200 units per kilogramme.

• Mucous membrane bleeding:

  • Every six hours for at least 24 hours, or until the bleeding is under control, administer 50 to 100 units/kg.
  • The daily dose cap is 200 units per kilogramme.

• Soft tissue hemorrhage (eg, retroperitoneal bleeding):

  • until bleeding is under control, provide 100 units/kg/dose intravenously every 12 hours.
  • The daily dose cap is 200 units per kilogramme.

• Other severe hemorrhages (eg, CNS bleeds):

  • until bleeding is under control, provide 100 units/kg/dose intravenously every 12 hours.
  • The daily dose cap is 200 units per kilogramme.

Perioperative management:

• Preoperative:

  • Given intravenously in a single dose of 50 to 100 units/kg just prior to surgery

• Postoperative:

  • Every 6 to 12 hours, administer 50 to 100 units/kg through intravenous until the bleeding is under control and the wound has healed.
  • The daily dose cap is 200 units per kilogramme.

FEIBA/ Autoplex Dose for Routine prophylaxis:

• Infants, Children, and Adolescents:
  • I85 units/kg/dose intravenous every alternate day

Pregnancy Risk Category: N

• Studies on animal reproduction have not been done.

Concentrated Activated Prothrombin Complex for Breastfeeding

• It is not known if breast milk contains the anti-inhibitor/coagulant complex.
• Manufacturer recommends caution when giving anti-inhibitorcoagulant complex to breastfeeding women.

Dose adjustment in renal disease:

There are no dosage adjustments provided in the manufacturer's labeling.

Dose adjustment in liver disease:

There are no dosage adjustments provided in the manufacturer's labeling.

Side effects of FEIBA/ Autoplex:

• Cardiovascular:

  • Chest Discomfort
  • Thrombosis (Arterial Thrombosis
  • Chest Pain
  • Flushing
  • Pulmonary Embolism
  • Hypertension
  • Myocardial Infarction
  • Tachycardia
  • Decreased Blood Pressure
  • Thromboembolism
  • Hypotension
  • Venous Thrombosis)
  • Cerebrovascular Accident (Embolic/Thrombotic Stroke)

• Central Nervous System:

  • Headache
  • Dizziness
  • Malaise
  • Drowsiness
  • Hypoesthesia (Including Facial)
  • Paresthesia
  • Chills

• Dermatologic:

  • Urticaria
  • Skin Rash
  • Pruritus

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Dysgeusia
  • Vomiting
  • Abdominal Distress

• Hematologic & Oncologic:

  • Disseminated Intravascular Coagulation

• Hypersensitivity:

  • Hypersensitivity Reaction (Including Anaphylaxis)
  • Angioedema

• Immunologic:

  • Antibody Development (Anamnestic Response)

• Local:

  • Pain At Injection Site

• Respiratory:

  • Cough
  • Wheezing
  • Bronchospasm
  • Dyspnea

• Miscellaneous:

  • Fever

Contraindication to FEIBA/ Autoplex:

• Hypersensitivity to anti-inhibitorcoagulant complexes or any formulation component, including elements from the kinin producing systems, is a contraindication.
• Anaphylaxis
• Acute thrombosis
• Myocardial Infarction
• Disseminated intravascularcoagulation
• embolism

Warnings and precaution

• Hypersensitivity reactions

  • After administration, hypersensitivity, allergic reactions, bronchospasm and circulatory shock may occur.
  • If you experience severe hypersensitivity reactions, the drug should be stopped immediately. Supportive care should also be given.

• Infusion reactions

  • Infusion reactions, such as hypertension/pyrexia/chills, can occur.

• Thromboembolic Events: [US Boxed Warning]

  • After treatment with anti-inhibitor complex, especially in higher doses, or in the presence of thrombotic risk factors, there have been reports of thromboembolic events, such as venous embolism, pulmonary embolism and stroke.
  • Patients should be monitored for thromboembolic symptoms, especially if they are receiving more than 200 units/kg/day.
  • Disseminated intravascularcoagulation/advanced atherosclerosis/ crush injury/sepsis should be treated with caution
  • Patients with >100 units/kg of disseminated intravascularcoagulation, acute coronary heart ischemia or thrombosis need to be monitored.
  • In a trial combining emicizumab with concurrent medication for breakthrough bleeding, several incidences of thrombotic microangiopathy were noted. Therefore, close monitoring is necessary when using this combination therapy.

Monitoring parameters:

• If more than 100 units/kg are administered, monitoring of bleeding control, signs and symptoms of disseminated intravascular coagulation, acute coronary ischemia, and thromboembolism should be considered.
• Other parameters including Hb and hematocrit/ hypotension/ hypersensitivity reactions should be noted

Note:

• Testing for hemostatic efficacy (APTT and TEG) is not useful for observing how the anti-inhibitor coagulant complex affects the body's responses.
• Disseminated intravascular coagulation may occur as a result of dosing to normalise these results.

How to administer FEIBA/Autoplex?

• Only for use with intravenous injection or infusion! Maximum rate of infusion: 2 units/kg/minute.
• Controlling the rate of administration requires the use of a syringe pump.
• As an anti-inhibitor coagulant complex that may adhere to the surface of glass syringes, plastic Luer lock syringes should be used.
• The medication shouldn't be administered in the same tube or container as other pharmaceuticals.
• The infusion should be finished in 180 minutes after reconstitution.

Mechanism of action of Activated Prothrombin concentrate complex (FEIBA, Autoplex):

• In patients with haemophilia treated with inhibitors, the anti-inhibitorcoagulant complex's many interactions result in the repair of defective thrombin generation.
• In vitro, the anti-inhibitor complex causes plasma containing factor VII inhibitor to have shorter activated partial thromboplastin times.

Initial: Peak thrombin production takes place in 15–30 minutes.

Time Based on thrombin generation, it can take between 8 and 12 hours.

Half-life elimination Based on thrombin generation, a time span of 4-7 hours.

Activated Prothrombin concentrate complex Brand Names (International):

• FEIBA
• Feiba NF
• Autoplex
• Autoplex-T
• Feiba Tim 4

Activated Prothrombin concentrate complex Brand Names in Pakistan:

No Brands Available in Pakistan.