Profilnine (Prothrombin Factor IX complex concentrate) is derived from human plasma that contains unactivated factors II, IX, and X. It is indicated for the treatment of Factor IX deficiency associated bleeding.

Indications of Unactivated 3 Factors Prothrombin complex concentrate (Profilnine):

• Factor IX deficiency (hemophilia B [Christmas disease]):

  • It is indicated for prevention and control of bleeding in patients with factor IX deficiency (hemophilia B or Christmas disease).
  • Limitations of use:
    • Not indicated for the treatment of other factor deficiencies (eg, factor II, VII, VIII, X), treatment of hemophilia A patients with inhibitors to factor VIII, or treatment of bleeding caused by low levels of liver-dependent coagulation factors.

• Off Label Use of Prothrombin in Adults:

  • Intracranial hemorrhage associated with warfarin;
  • Life-threatening hemorrhage associated with warfarin

Prothrombin complex (Profilnine) Dosage in adults:

Note:

• Factor IX complex (Human) [Factors II, IX, X] (Bebulin, Profilnine) contains low or non-therapeutic levels of factor VII component whereas Prothrombin Complex Concentrate (Human) [(Factors II, VII, IX, X), Protein C, Protein S] (Kcentra, Octaplex) which contains therapeutic levels of factor VII.

Prothrombin complex (Profilnine) Treatment dose in the Control or prevention of bleeding in patients with factor IX deficiency (hemophilia B [Christmas disease]):

The dose depends on clinical condition, the severity of factor IX deficiency, extent, and location of bleeding. Close monitoring of the factor IX level is necessary. If multiple doses are required, it should be given at a 24-hour interval.

• The formula for units required to raise blood level %:

  • Bebulin:
    • In general, factor IX 1 unit/kg will increase the plasma factor IX level by 0.8%.
    • Number of Factor IX units required = body weight (kg) x desired factor IX increase (as % of normal) x 1.2 units/kg.
  • Profilnine:
    • In general, factor IX 1 unit/kg will increase the plasma factor IX level by 1%.
    • Number of factor IX units required = bodyweight (kg) x desired factor IX increase (as % of normal) x 1 unit/kg
    • For example, to increase factor IX level to 25% of normal in a 70 kg patient: Number of factor IX units needed = 70 kg x 25 x 1 unit/kg = 1,750 units
    • As a general rule, the level of factor IX required for treatment of different conditions is listed below:

  • Hemorrhage:

    • Minor bleeding (early hemarthrosis, minor epistaxis, gingival bleeding, mild hematuria):

      • Bebulin:
        • Raise factor IX level to 20% of normal (typical initial dose: 25 to 35 units/kg I/V) average duration of treatment is 24 hours.
        • A single dose is usually sufficient or a second dose may be given after 24 hours.
      • Profilnine:
        • Raise factor IX level to 20% to 30% of normal (initial dose: 20 to 30 units/kg) every 16 to 24 hours for 1 to 2 days for minor hemorrhage or until hemorrhage stops and healing has been achieved.

Moderate bleeding (severe joint bleeding, early hematoma, major open bleeding, minor trauma, minor hemoptysis, hematemesis, melena, major hematuria):

• Bebulin:
  • Raise factor IX level to 40% of normal (typical initial dose: 50 to 65 units/kg I/V);
  • the average duration of treatment is 2 days or until adequate wound healing.
• Profilnine:
  • Raise factor IX level to 20% to 30% of normal (initial dose: 20 to 30 units/kg I/V) every 16 to 24 hours for 2 to 7 days for moderate hemorrhage or until hemorrhage stops and healing has been achieved.

  • Major bleeding (severe hematoma, major trauma, severe hemoptysis, hematemesis, melena):

    • Bebulin:
      • Raise factor IX level to ≥60% of normal (typical initial dose: 75 to 90 units/kg I/V );
      • The average duration of treatment is 2 to 3 days or until adequate wound healing.
    • Profilnine:
      • Raise factor IX level to 30% to 50% of normal (initial dose: 30 to 50 units/kg I/V) every 16 to 24 hours;
      • following this treatment period, maintain factor IX levels at 20% of normal (maintenance dose: 20 units/kg) for 3 to 10 days or until healing has been achieved.

  • Surgical procedures:

    • Dental surgery:

      • Bebulin:
        • Raise factor IX level to 40% to 60% of normal on the day of surgery (typical dose: 50 to 75 units/kg I/V).
        • One infusion one hour before surgery is adequate for single tooth removal while replacement therapy for one week is required for the extraction of multiple teeth.
      • Profilnine:
        • Raise factor IX level to 50% of normal immediately prior to the procedure;
        • maintain factor IX levels at 30% to 50% of normal (maintenance dose: 30 to 50 units/kg I/V) every 16 to 24 hours for 7 to 10 days following surgery or until healing has been achieved.

    • Minor surgery:

      • Bebulin:
        • Raise factor IX level to 40% to 60% of normal on the day of surgery (typical initial dose: 50 to 75 units/kg I/V).
        • Decrease factor IX level from 40% to 60% of normal to 20% to 40% of normal during the initial postoperative period (1 to 2 weeks or until adequate wound healing) [typical dose: 26 to 65 units/kg].
        • The preoperative dose should be given 1 hour before surgery. The average dosing interval maybe every 12 hours initially, then every 24 hours later in the postoperative period.
      • Profilnine:
        • Raise factor IX level to 30% to 50% of normal (initial dose: 30 to 50 units/kg I/V ) prior to surgery.
      • (Note: Surgery type not specified by the manufacturer); maintain factor IX levels at 30% to 50% of normal (maintenance dose: 30 to 50 units/kg I/V) every 16 to 24 hours for 7 to 10 days following surgery or until healing is achieved.

    • Major surgery:

      • Bebulin:
        • Raise factor IX level to ≥60% of normal on the day of surgery (typical initial dose: 75 to 90 units/kg I/V).
        • Decrease factor IX level from ≥60% of normal to 20% to 60% of normal during the initial postoperative period (1 to 2 weeks) [typical dose: 25 to 75 units/kg];
        • A further decrease to maintain a factor IX level of 20% of normal during late postoperative period (≥3 weeks) and continuing until appropriate wound healing. [typical dose: 25 to 35 units/kg].
        • The preoperative dose should be given 1 hour before surgery. The average dosing interval maybe every 12 hours initially, then every 24 hours later in the postoperative period.
      • Profilnine:
        • Raise Factor IX level to 30% to 50% of normal (initial dose: 30 to 50 units/kg I/V) before surgery.
      • (Note: Surgery type not specified by the manufacturer); maintain factor IX levels at 30% to 50% of normal (maintenance dose: 30 to 50 units/kg I/V) every 16 to 24 hours for 7 to 10 days following surgery or until healing is achieved.

Prothrombin complex (Profilnine) in life-threatening hemorrhage associated with warfarin (off-label):

Note:

• Fresh frozen plasma (FFP) or factor VIIa should be given due to a non-therapeutic level of factor VII component in the product.
• 1 to 2 units of FFP should be given for immediate INR reversal in combination with vitamin K 5 to 10 mg by slow IV infusion and repeated every 12 hours if INR is persistently elevated.
• Factor IX complex (human) dosing has not been established in this setting; the following regimens have been used with some success.

• The following 2 methods have been suggested, but are not product-specific:

  • Adjusted-dose weight-based regimen:

    • INR <2: 20 units/kg
    • INR 2 to 4: 30 units/kg
    • INR >4: 50 units/kg

Note: Dose should be repeated if  INR remains >1.5

• May also determine dose based on presenting INR and estimated functional prothrombin complex (PC) expressed as a percentage of normal plasma levels:

  • Units needed to be infused = (target % of functional PC to be reached – current estimated % of functional PC) x kg of body weight.

Conversion of the INR to Estimated Functional Prothrombin Complex (PC)

Prothrombin complex (Profilnine) dose in the treatment of Intracranial hemorrhage associated with warfarin (off-label):

• Fixed-dose weight based regimen:

  • INR ≥1.4: 50 units/kg;
  • Repeat INR within 15 to 60 minutes and serially every 6 to 8 hours for the next 24 to 48 hours.
  • FFP should be used if INR remains ≥1.4 within the first 24 to 48 hours after the initial dose.
  • Factor IX complex (PCC) alone is recommended for initial reversal.

Prothrombin complex (Profilnine) Dosage in children:

Prothrombin complex (Profilnine) dose in the treatment of Hemophilia B:

• Children and Adolescents:

  • The formula for units required to raise blood level %:

    • Bebulin® VH: In general, 1 unit/kg of factor IX will increase the plasma factor IX level by 0.8%.
      • Number of Factor IX units required = body weight (kg) x desired factor IX increase (as % of normal) x 1.2 units/kg.
      • For example, to increase factor IX level to 25% of normal in a 70 kg patient: Number of factor IX units needed = 70 kg x 25 x 1.2 unit/kg = 2100 units.
    • Profilnine® SD: In general, 1 unit/kg of factor IX will increase the plasma factor IX level by 1%.
      • Number of factor IX units required = bodyweight (kg) x desired factor IX increase (as % of normal) x 1 unit/kg.
      • For example, to increase factor IX level to 25% of normal in a 70 kg patient,Number of factor IX units needed = 70 kg x 25 x 1 unit/kg = 1750 units.
    • As a general rule, the level of factor IX required for treatment of different conditions is listed below:

  • Hemorrhage:

    • Minor bleeding (early hemarthrosis, minor epistaxis, gingival bleeding, mild hematuria):

      • Bebulin® VH: Raise factor IX level to 20% of normal [typical initial dose: 25-35 IV units/kg], generally a single dose is sufficient.
      • Profilnine® SD: Mild to moderate bleeding: Raise factor IX level to 20% to 30% of normal, generally a single dose is sufficient.

    • Moderate bleeding (severe joint bleeding, early hematoma, major open bleeding, minor trauma, minor hemoptysis, hematemesis, melena, major hematuria):

      • Bebulin® VH: Raise factor IX level to 40% of normal [typical initial dose: 40-55 units/kg I/V], the average duration of treatment is 2 days or until adequate wound healing.
      • Profilnine® SD: Mild to moderate bleeding: Raise factor IX level to 20% to 30% of normal.

    • Major bleeding (severe hematoma, major trauma, severe hemoptysis, hematemesis, and melena):

      • Bebulin® VH: Raise factor IX level to ≥60% of normal [typical initial dose: 60-70 units/kg I/V], the average duration of treatment is 2-3 days or until adequate wound healing. Do not raise >60% in patients who may be predisposed to thrombosis.
      • Profilnine® SD: Raise factor IX level to 30% to 50% of normal, daily infusions are usually required.

    • Surgical procedures:

      • Dental surgery:

        • Bebulin® VH: Raise factor IX level to 40% to 60% of normal on the day of surgery [typical dose: 50-60 units/kg I/V]. For single tooth removal, one infusion is given 1 hour before surgery is adequate. While one week of replacement therapy is needed for the extraction of multiple teeth (see dosing guidelines for Minor Surgery).
        • Profilnine® SD: Raise factor IX level to 50% of normal immediately prior to the procedure, administer additional doses if bleeding recurs.

      • Minor surgery:

        • Bebulin® VH:
          • Raise factor IX level to 40% to 60% of normal on the day of surgery [typical initial dose: 50-60 units/kg I/V].
          • Decrease factor IX level from 40% of normal to 20% of normal during the initial postoperative period (1-2 weeks or until adequate wound healing) [typical dose: 55 units/kg decreasing to 25 units/kg I/V].
          • The preoperative dose should be given 1 hour before surgery.
          • The average dosing interval maybe every 12 hours initially, then every 24 hours later in the postoperative period.
        • Profilnine® SD:
          • Raise factor IX level to 30% to 50% of normal for at least 7 days after surgery.

      • Major surgery:

        • Bebulin® VH:
          • Raise factor IX level to ≥60% of normal on the day of surgery [typical initial dose: 70-95 units/kg I/V].
          • Do not raise >60% in patients who may be predisposed to thrombosis.
          • Decrease factor IX level from 60% of normal to 20% of normal during the initial postoperative period (1-2 weeks) [typical dose: 70 units/kg decreasing to 35 units/kg];
          • A further decrease to maintain a factor IX level of 20% of normal during the late postoperative period (≥3 weeks) and continuing until adequate wound healing is achieved [typical dose: 35 units/kg decreasing to 25 units/kg].
          • The preoperative dose should be given 1 hour before surgery.
          • The average dosing interval maybe every 12 hours initially, then every 24 hours later in the postoperative period.
        • Profilnine® SD:
          • Raise factor IX level to 30% to 50% of normal for at least 1 week after surgery.

Prothrombin complex (Profilnine) Dose in bleeding Prophylaxis (long-term management):

• Bebulin® VH: 20-30 units/kg/dose I/V once or twice a week may reduce the frequency of spontaneous hemorrhage; the dosing regimen should be individualized.

Pregnancy Risk Factor C

• Patients with inherited coagulation disorders or pregnancy complications are at greater risk of bleeding after an abortion, invasive procedure, miscarriage or delivery.
• At the first antenatal appointment, during the third trimester and after delivery, monitoring of the clotting factors will be necessary.
• If factor IX concentrations exceed 0.5 IU/mL then replacement procedures are required.
• It is important to maintain hemostatic factor IX levels for at least three to five days after a postpartum procedure or invasive procedure.
• Recombinant products are desirable when replacement with a factor IIX concentrate is necessary to increase factor IX during pregnancy.
• Concentrations of pure factor IX are preferable to those containing factor II, VII and IX (also known by PCCs).
• During pregnancy, Factor II concentrations don't increase.
• PCC should only be administered to factor II activity below 0.2 IU/mL during labor or before cesarean birth.
• If given before pregnancy, PCCs may be continued to be used.
• Pregnancy is characterized by an increase in factor X levels. However, patients with severe factor-X deficiencies are still at risk of bleeding.
• Replacement is necessary if factor X concentrations are below 0.3 IU/mL during the procedure or before.
• It is important to maintain hemostatic concentrations at least three days after procedures or postpartum.
• PCCs can be used during pregnancy to treat severe factor X deficiencies.

Prothrombin complex (Profilnine) Dose adjustment in renal disease:

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

Prothrombin complex (Profilnine) Dose adjustment in liver disease:

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

Side effects of Prothrombin complex (Profilnine):

• Cardiovascular:

  • Flushing
  • Thrombosis (Sometimes Fatal)

• Central Nervous System:

  • Chills
  • Drowsiness
  • Headache
  • Lethargy
  • Paresthesia

• Dermatologic:

  • Skin Rash
  • Urticaria

• Gastrointestinal:

  • Nausea
  • Vomiting

• Hematologic & Oncologic:

  • Disseminated Intravascular Coagulation
  • Heparin-Induced Thrombocytopenia (With Products Containing Heparin)

• Hypersensitivity:

  • Anaphylactic Shock

• Immunologic:

  • Antibody Development (To Clotting Factor)

• Respiratory:

  • Dyspnea

• Miscellaneous:

  • Fever

Contraindications to Prothrombin Complex Concentrate(Profilnine):

Profilnine:

• The manufacturer's labeling does not list any contraindications.

Bebulin:

• Hypersensitivity reactions or allergy to factor IX or any component of formulation; heparin allergy or history of heparin induced thrombocytopenia.

Warnings and precautions

• Formation of antibodies:

  • Factor IX therapy may result in the formation of factor IX antibodies in the first 10-20 exposure days.
  • However, there is a greater risk of severe hypersensitivity reactions in these patients.
  • If the patient has had a suboptimal clinical response or is about to have a surgery, screening for inhibitors may be necessary.
  • Patients with severe hemophilia are at greater risk than those with milder or moderate hemophilia.

• Hypersensitivity reactions

  • It can lead to severe hypersensitivity and anaphylactic/anaphylactoid reactions.
  • Infusions may cause delayed reactions in patients who have not been treated before.
  • Due to the possibility of allergic reactions, it is important to perform the initial 10-20 administrations under medical supervision.
  • Factor IX inhibitor development may cause hypersensitivity reactions. Patients with allergic reactions should be tested for factor IX inhibitors.
  • In the event of fatal hypersensitivity reactions, alternative measures should be taken.

• Thrombotic events

  • Prothrombin is well-known for its ability to cause thrombotic events, including deep vein thrombosis and pulmonary embolism.
  • Patients with congenital and acquired coagulation disorders are at greater risk of receiving repeated high doses.
  • It should not be used in patients with DIC, hepatic dysfunction, coronary artery disease or pre- or postoperatively.
  • Infusions should be monitored regularly and stopped immediately if there are any signs or symptoms that could indicate thrombosis.

• Hepatic impairment

  • Patients with hepatic impairment should not use it due to the possibility of thromboembolic complications.

Monitoring parameters:

Levels of factor IX, PT, PTT, INR (when used for warfarin reversal) Signs and symptoms of hypersensitivity reactions, DIC, thrombosis, especially in patients with liver disease, surgical patients, and patients with known risk factors predisposing to thrombosis.

How to administer the Prothrombin Complex Concentrate?

• The solution should be given intravenously at room temperature at a rate no more than 2 mL/minute for Bebulin or 10 mL/minute for Profilnine.
• A rapid infusion can lead to vasomotor reactions, therefore the recommended infusion rates should not be exceeded.
• Adverse reactions can be minimized by slowing the rate of infusion, changing a lot of medication, antihistamine administration.

Mechanism of action of Prothrombin Complex Concentrate:

• Prothrombin can replace deficient clotting factor(s) such as factor X, hemophilia A, or Christmas disease (X-linked recessive disorder blood coagulation, characterized by an abnormal or insufficient synthesis of the clotting factor factor IX).
• Factor IX, a vitamin K-dependent cocoagulation factor, is synthesized in liver and activated in intrinsic coagulation pathway by factor XIa.
• The activation of factor IX (IXa), and factor VII,C results in the conversion of prothrombin to thrombin, which leads to the formation a fibrin-clot.
• Infusions of exogenous factor VIII are temporarily used to restore hemostasis. This is done to correct the hemophilia B.

Half-life elimination:

• IX component: 19 to 25 hours

International Brands of Prothrombin Complex Concentrate:

• Bebulin
• Profilnine
• Profilnine SD
• Profilnine SD
• Prothrombinex-VF
• Prothromplex
• Prothromplex Total NF
• Protromplex
• TBSF

Prothrombin Complex Concentrate Brand Names in Pakistan:

No Brands Available in Pakistan.