Coagulation factor IX (human).
MonoFIX-VF is prepared from blood collected from voluntary donors. The factor IX in MonoFIX-VF is purified using ion exchange and heparin affinity chromatography to remove other vitamin K-dependent factors eg, factors II, VII and X. The manufacturing process of MonoFIX-VF includes a solvent detergent (tri-butyl phosphate and polysorbate 80) treatment and a virus filtration step to reduce the potential for viral transmission, particularly of hepatitis A virus.
When reconstituted as recommended, each vial nominally contains: Factor IX 500 IU, heparin 50-140 IU, antithrombin III 12.5 IU, plasma proteins ≤20 mg, sodium 120 mmol/L, phosphate 20 mmol/L, citrate 10 mmol/L and chloride 50 mmol/L.
Pharmacology: Human factor IX is a single-chain glycoprotein with a molecular weight of 68 kilodalton. It is synthesised in the liver, like other vitamin K-dependent proteins and participates in the intrinsic blood coagulation pathway. Factor XIa activates factor IX, which then, in the presence of factor VIIIa, activates factor X. This leads to the conversion of prothrombin to thrombin and the formation of a fibrin clot.
Haemophilia B (also known as Christmas disease) is an X-linked recessive blood coagulation disorder. It is caused by reduce factor IX activity through either insufficient or abnormal synthesis of the factor IX protein. Clinical symptoms of haemophilia B, include skin bruising, excessive haemorrhage after trauma and spontaneous haemorrhage into joints, muscles or internal organs. Excessive and severe haemorrhage can cause orthopaedic deformity, organ dysfunction or death.
Studies in animals indicate that the potential thrombogenicity of MonoFIX-VF is lower than prothrombin complex concentrates (PCCs). In a study where the in vivo generation of rat fibrinopeptide A was used as a marker of thrombogenicity, MonoFIX-VF administered at a dose of 300 IU factor IX/kg body weight did not elevate plasma fibrinopeptide A concentration 60 min post-infusion and was equivalent to the negative control, 20% human albumin. In contrast, PCCs used as positive controls raised plasma fibrinopeptide A concentration by a factor of 30-70 times over pre-infusion values. In a modified Wessler rabbit stasis model of thrombogenicity, MonoFIX-VF showed no evidence of thrombogenicity in any of the experiments when tested at a dose of 200 IU factor IX/kg body weight. In comparison, activated factor IX concentrates used for positive control were thrombogenic in all experiments.
Clinical Trials: CSL has performed clinical trials with MonoFIX-VF and MonoFIX. MonoFIX-VF includes a viral filtration step. This step is not included in the manufacturing process for MonoFIX. MonoFIX-VF has been the subject of the extensive biochemical characterisation to demonstrate that the active ingredient is equivalent to MonoFIX.
The pharmacokinetics of MonoFIX-VF have been determined in an open multicentre study, following a single IV infusion of 50 IU/kg in 12 participants >12 years with haemophilia B. The estimated half-life and recovery of factor IX were approximately 24 hrs and 60%, respectively.
Clinical efficacy and safety were studied in a clinical trial using MonoFIX. The trial included 11 immunocompetent male patients with moderate to severe haemophilia B. All patients had been previously treated with factor IX concentrates and were aged from 2-52. Patients used MonoFIX as required basis for a period of 6 months. No patients undergoing surgery were included in the trial. There is some evidence that recovery of factor IX in patients undergoing surgery may be reduced.
During the 6 months of the trial, there were a total of 233 administrations of MonoFIX of which 218 were assessed for effectiveness. Treatment was considered to be effective by the patient or his guardian in 98% of administrations. For safety data from this trial (see Adverse Reactions).
No inhibitor studies have been carried out in humans using MonoFIX-VF. However, in the clinical trial of MonoFIX, 1 patient had evidence of transient inhibitor development in the post-study period. Repeat pharmacokinetic studies were not performed.
For the treatment of haemorrhages, for use in surgery and as a prophylaxis in patients with haemophilia B. MonoFIX-VF is not indicated for the treatment of factor II, VII or X deficiencies because it does not contain therapeutic levels of these coagulation factors. MonoFIX-VF is not indicated for the treatment of haemophilia A patients with factor VIII inhibitors.
The following recommendations for doses as a general guideline for therapy are provided in table as follows (see Table 1). The exact loading and maintenance doses and dosing intervals should be based on the patient's clinical condition and response to therapy. Laboratory tests should be performed to ensure that the desired plasma factor IX concentrations are achieved.
Click on icon to see table/diagram/image
Limited clinical data exists on the use of MonoFIX-VF administered by continuous infusion. Based on 24-hr stability studies conducted in the laboratory, it is suggested that this method may be suitable for covering surgical procedures. The product required should be reconstituted to the same volume and in the same diluent as for bolus infusion and infused using an infusion pump suitable for this volume. Reconstitution should be done under aseptic conditions and sterile integrity of the delivery device should be maintained.
It is recommended that the plasma factor IX concentrations be monitored during treatment for more severe haemorrhage. Monitoring of plasma factor IX concentrations is also recommended for patients undergoing surgery.
With the MonoFIX-VF vial upright, attach a plastic disposable syringe to the filter transfer set (transparent plastic part). Invert the system and draw the reconstituted MonoFIX-VF into the syringe by pulling the plunger back slowly. One large syringe may be used to pool several vials of reconstituted MonoFIX-VF.
Once the MonoFIX-VF has been transferred into the syringe, firmly hold the barrel of the syringe (keeping the syringe plunger facing down) and detach the filter transfer set from the syringe. Discard the filter transfer set (transparent plastic part) and empty MonoFIX-VF vial in an appropriate waste container. Fit the syringe to a suitable injection needle to administer the reconstituted MonoFIX-VF. Do not use the filter transfer set for injection.
Give the dose slowly (approximately 3 mL/min or as tolerated by the patient) by the IV route. Slow the rate of infusion or stop the infusion if any sign of intolerance is recognised. When the contents of >1 vial are to be given, it will be convenient to pool the total amount prior to administration in a large syringe or sterile bag. This must be done aseptically.
To reduce microbiological hazard, use as soon as practicable after reconstitution/preparation. The solution must not be stored and, unless reconstitution has been done under aseptic conditions and sterile integrity of the delivery device has been maintained, infusion should be completed within 3 hrs of reconstitution in the case of routine use. For use in surgery, the conditions described under Continuous Infusion mentioned previously can apply. Any unused portion remaining in the vial must be discarded appropriately.
The solution must not be added or mixed with any other fluids to be given, including whole blood.
High doses of products containing factor IX have been associated with instances of myocardial infarction, disseminated intravascular coagulation (DIC), venous thrombosis and pulmonary embolism. Overdosage with MonoFIX-VF may potentially enhance the risk of these complications.
MonoFIX-VF should be used with caution in patients with a previous or known severe allergy to factor IX concentrates.
High doses of PCCs have been associated with DIC. Although MonoFIX-VF contains purified factor IX, the potential risk of thrombosis and DIC should be recognised. The use of products containing factor IX could be hazardous in patients with a history of fibrinolysis, myocardial infarction (MI), DIC or liver disease.
The reported prevalence for the formation of neutralising antibodies (inhibitors) in patients receiving plasma-derived factor IX is approximately 4%. Patients should be monitored for the development of factor IX inhibitors. If the expected factor IX activity plasma levels are not attained or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor IX inhibitor is present. In patients with high levels of inhibitor, factor IX replacement therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of patients with haemophilia.
There has been no clinical experience with MonoFIX-VF with respect to inhibitor development in previously untreated patients.
Check the following before use: Prior to using MonoFIX-VF for the 1st time, the hepatitis A and hepatitis B antibody status of recipients should be tested. Immunisation with hepatitis A and hepatitis B vaccine is recommended for patients with no antibodies to these viruses.
MonoFIX-VF contains heparin sodium 50-140 IU in each reconstituted vial. Heparin is known to cause thrombocytopenia and this possibility should be considered if thrombocytopenia develops during treatment. Consideration should be given to the clinical effect of heparin if high doses of MonoFIX-VF are required.
Pathogen Safety: MonoFIX-VF is made from human plasma. Products made from human plasma may contain infectious agents eg, viruses and theoretically Creutzfeldt-Jakob disease (CJD) agents, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain infectious agents and by testing for the presence of certain virus markers.
In addition, virus removal and inactivation procedures are included in the manufacturing process. The current procedures applied in the manufacture of MonoFIX-VF are effective against enveloped viruses eg, HIV (human immunodeficiency virus), hepatitis B and hepatitis C viruses, and the non-enveloped virus hepatitis A. It is also known to have some effect on the removal of the non-enveloped virus, parvovirus B19.
Despite these measures, such products may still potentially transmit disease. There is also the possibility that other known or unknown infectious agents may be present in such products.
Vaccination for patients in receipt of medicinal products from human plasma should be considered where appropriate.
Carcinogenicity, Mutagenicity & Impairment of Fertility: The potential carcinogenicity, mutagenicity and reproductive toxicity of MonoFIX-VF have not been established in appropriate studies.
Use in pregnancy & lactation: MonoFIX-VF contains heparin sodium. An increased incidence of foetal loss and prematurity may be associated with heparin-induced maternal haemorrhage. The safe use of MonoFIX-VF during human pregnancy or lactation has not been established in appropriate studies.
Use in children: The use of MonoFIX-VF in children has not been established in appropriate studies.
Use in the elderly: The use of MonoFIX-VF in elderly has not been established in appropriate studies.
MonoFIX-VF contains heparin sodium. An increased incidence of foetal loss and prematurity may be associated with heparin-induced maternal haemorrhage. The safe use of MonoFIX-VF during human pregnancy or lactation has not been established in appropriate studies.
Allergic, anaphylactic reactions or fever are rarely observed in patients receiving factor IX preparations. If any adverse event occurs while MonoFIX-VF is being administered, the rate of injection should be slowed or stopped to alleviate symptoms.
Heparin is known to cause thrombocytopenia and this possibility should be considered if thrombocytopenia develops during treatment.
Adverse events were monitored in a pharmacokinetic study with MonoFIX-VF, however, none were reported.
Adverse events were also monitored during a 2-part safety, efficacy and tolerability clinical trial for MonoFIX in 11 patients with moderate to severe haemophilia B. In the 2nd part of the trial where MonoFIX was administered on as required basis for a period of 6 months, 31 adverse events were recorded from a total of 233 administrations. These events occurred in 9 of the 11 patients and have been presented in the table. (See Table 2.)
Click on icon to see table/diagram/image
During post-marketing surveillance of MonoFIX-VF, the following adverse events have also been reported; injection site reactions, cold clammy skin, nausea, dizziness and taste disturbances.
The interaction of MonoFIX-VF with other drugs has not been established in appropriate studies.
Effects on Laboratory Tests: MonoFIX-VF is formulated with heparin sodium and antithrombin III. Therefore, the results of anticoagulation tests should be interpreted with care.
Reconstitution: Before reconstitution, allow the vial of MonoFIX-VF and container of water for injections to reach a temperature between 20-30°C. Remove the dust covers from the tops of the MonoFIX-VF and water for injections vials.
Apply a suitable antiseptic to the exposed part of the rubber stoppers of both MonoFIX-VF and water for injections and allow to dry.
Open the outer package of the Mix2Vial filter transfer set by peeling away the lid. If the seal of the lid is not intact or there are any concerns about its integrity, do not use the filter transfer set, but return it to the appropriate blood transfusion service. Place the water for injections on a level surface and hold the vial firmly. Take the filter transfer set together with its outer package and invert it. Push the blue plastic cannula of it firmly through the rubber stopper of the water for injections.
While holding onto the vial of water for injections, carefully remove the outer package from the filter transfer set, being careful to leave it firmly attached to the water for injections' vial. Ensure that only the package and not the filter transfer set is removed.
With the MonoFIX-VF vial held firmly on a level surface, invert the water for injections with the filter transfer set attached and push the transparent plastic cannula end of it firmly through the MonoFIX-VF stopper. The water will be drawn into the vial by the vacuum within. In the unlikely event that the vial does not contain a vacuum, do not use the product, but return it to the appropriate blood transfusion service.
With the water for injections and MonoFIX-VF vials still attached, gently swirl the product vial to ensure that the product is fully dissolved. Avoid excessive frothing. A clear or slightly opalascent solution is usually obtained in 10 min or less. The solution should be used immediately (see Administration).
Once the contents of the MonoFIX-VF vial are completely dissolved, firmly hold both the transparent and blue parts of the filter transfer set. Unscrew it into 2 separate pieces and discard the empty water for injections vial and the blue part of the filter transfer set in an appropriate waste container. The Mix2Vial is intended to filter the contents of a single vial of MonoFIX-VF only. If multiple vials of MonoFIX-VF are to be administered, a separate Mix2Vial must be used for each vial.
Do not refrigerate MonoFIX-VF once it has been reconstituted.
MonoFIX-VF contains no antimicrobial agent. It must, therefore, be used immediately after reconstitution. Any unused solution should be discarded appropriately. Use in 1 patient on 1 occasion only. If clots or a gel form, do not use MonoFIX-VF but return it to the appropriate blood transfusion service.
Spillage or Breakages: Should a break in the container or spillage occur, due precautions should be taken to avoid contamination of cuts and abrasions, as well as to avoid inhalation or swallowing of the spillage. Adequate disinfection can be obtained with the application of sodium hypochlorite 1% for 15 min. Commercial bleaches may be diluted appropriately to obtain this concentration.
Do not use after the expiry date.
Store at 2-8°C. Refrigerate. Do not freeze. Protect from light.
B02BD04 - coagulation factor IX ; Belongs to the class of blood coagulation factors. Used in the treatment of hemorrhage.
Powd for inj (vial, sterile, freeze-dried powd) 500 IU/10 mL x 1's.