This information is intended for use by health professionals
Treatment monitoringDuring the course of treatment, appropriate determination of factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to factor IX, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor IX activity) is indispensable.
PosologyDose and duration of the substitution therapy depend on the severity of the factor IX deficiency, on the location and extent of the bleeding and on the patient´s clinical condition. The number of units of factor IX administered is expressed in International Units (IU), which are related to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor IX in plasma). One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX in one ml of normal human plasma.
On demand treatmentThe calculation of the required dosage of factor IX is based on the empirical finding that 1 International Unit (IU) factor IX per kg body weight raises the plasma factor IX activity by 1-2 % of normal activity. The required dose is determined using the following formula:
Required units = body weight (kg) x desired factor IX rise (%) (IU/dl) x 0.8The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case. In the case of the following haemorrhagic events, the factor IX activity should not fall below the given plasma activity level (in % of normal or in IU/dl) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:
|Degree of haemorrhage/ Type of surgical procedure||Factor IX level required (%) (IU/dl)||Frequency of doses (hours)/Duration of therapy (days)|
|Early haemarthrosis, muscle bleeding or oral bleeding||20 - 40||Repeat every 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.|
|More extensive haemarthrosis, muscle bleeding or haematoma||30 - 60||Repeat infusion every 24 hours for 3 - 4 days or more until pain and acute disability are resolved.|
|Life threatening haemorrhages||60 - 100||Repeat infusion every 8 to 24 hours until threat is resolved.|
|Minor surgery including tooth extraction||30 - 60||Every 24 hours, at least 1 day, until healing is achieved.|
|Major surgery||80 - 100 (pre- and post-operative)||Repeat infusion every 8 to 24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor IX activity of 30 to 60% (IU/dl).|
ProphylaxisFor long term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 20 to 40 IU of factor IX per kilogram of body weight at intervals of 3 to 4 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.
Paediatric populationThere are insufficient data to recommend the use of Haemonine® in children less then 6 years of age. Method of administrationIntravenous use. For instructions on dilution of the medicinal product before administration, see section 6.6. It is recommended to not exceed a maximal infusion rate of 5 ml/min.
InhibitorsAfter repeated treatment with human coagulation factor IX products, patients should be monitored for the development of neutralising antibodies (inhibitors) that should be quantified in Bethesda Units (BU) using appropriate biological testing. There have been reports in the literature showing a correlation between the occurrence of a factor IX inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an increased risk of anaphylaxis with subsequent challenge with factor IX.Because of the risk of allergic reactions with factor IX products, the initial administrations of factor IX should, according to the treating physician's judgement, be performed under medical observation where proper medical care for allergic reactions could be provided.
ThromboembolismBecause of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to new-born infants, or to patients at risk of thrombotic phenomena or DIC. In each of these situations, the benefit of treatment with Haemonine should be weighed against the risk of these complications.Due to potential additive or synergistic pharmacodynamic effects, coadministration of antifibrinolytic agents with anti-inhibitor coagulant complex or factor IX complex could increase the risk of thrombosis.
Cardiovascular eventsIn patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the cardiovascular risk.
Catheter-related complicationsIf a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.
Transmissible agentsStandard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens. The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped hepatitis A virus (HAV).The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (fetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia). Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived factor IX products.It is strongly recommended that every time that Haemonine® is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.
Paediatric populationThe listed warnings and precautions apply both to adults and children aged 6 years and older (see also section 4.2).This medicinal product contains a maximum of 4.9 mmol (113 mg) sodium per standard dose of 2000 IU. To be taken into consideration by patients on a controlled sodium diet.
Paediatric populationThe listed interactions apply both to adults and children aged 6 years and older (see also section 4.2).
Summary of the safety profileHypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, , generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely and may in some cases progress to severe anaphylaxis (including shock).. In some cases, these reactions have progressed to severe anaphylaxis, and they have occurred in close temporal association with development of factor IX inhibitors (see also section 4.4). Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reaction. Haemonine may contain traces of heparin below the limit of quantitation (0.1 IU/ml) which may cause hypersensitivity reactions and reduced blood cell counts which may affect the blood clotting system. Patients with a history of heparin-induced allergic reactions should avoid the use of heparin-containing medicines.Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.There is a potential risk of thromboembolic episodes following the administration of factor IX products, with a higher risk for low purity preparations. The use of low purity factor IX products has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX is rarely associated with such side effects. For safety information with respect to transmissible agents, see section 4.4.
Tabulated list of adverse reactionsFrequencies have been evaluated according to the following convention:
|Common:||≥1/100 to <1/10|
|Uncommon:||≥1/1,000 to <1/100|
|Rare:||≥1/10,000 to <1/1,000|
|not known||cannot be estimated from the available data|
|MedDRA Standard System Organ Class||Frequency||Adverse reactions|
|Immune system disorders||very common*||Hypersensitivity|
|Nervous system disorders||common||Hyperaesthesia|
|Skin and subcutaneous tissue disorders||common||Dermatitis allergic, Urticaria|
|Musculoskeletal and connective tissue disorders||common||Back pain|
|Vascular disorders||common||Hot flush|
|Respiratory, thoracic and mediastinal disorders||common||Dyspnoea|
|General disorders and administration site conditions||common||Feeling cold, Injection site reaction (including e.g. pain and rash)|
|Investigations||not known**||factor IX inhibition|
Description of selected adverse reactions
Factor IX inhibitionThe development of inhibitory antibodies is a known complication in the management of individuals with haemophilia B. There is no experience with previously untreated patients (PUPs) so far. During clinical development no factor IX inhibitor induction was observed in previously treated patients (PTPs, n=36) during 1,493 exposure days.
Paediatric populationFrequency, type and severity of adverse reactions in children aged 6 years and older are expected to be the same as in adults (see also section 4.2). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V*.
Paediatric populationThere are insufficient data to recommend the use of Haemonine® in children less than 6 years of age.
|Dissolution of the concentrate: • Bring the unopened vials of the solvent (water for injections) and product to room temperature. If a water bath is used for warming, it must be scrupulously ensured that the water does not come into contact with the caps or stoppers of the vials. Otherwise contamination of the medicine may occur. • Remove the caps from both vials in order to expose the central portions of the rubber stoppers (1). Ensure that the rubber stoppers of the product and solvent vials are treated with a disinfectant. • Remove the top of the transfer system packaging (2). Place the blue part of the transfer system onto the upright standing vial containing the solvent (3). • Remove the remaining part of the packaging of the transfer system. Now the transparent part of the transfer system is visible. • Place the product vial on an even surface. • Turn the combination of transfer system and solvent vial upside down. Push the spike of the transparent part of the adapter straight down through the product vial stopper (4). The vacuum present in the product vial causes the solvent to flow into the product vial. (5) Immediately unscrew the blue part of the transfer system together with the solvent vial. Discard the solvent vial with the blue part of the transfer system attached (6). Gently swirling the product vial helps in dissolving the powder. Do not shake vigorously, all foaming is to be avoided! The solution is clear or slightly opalescent. The solution ready for use must be used immediately after dissolving. Do not use solutions that are cloudy or have deposits.|
|Injection: • Once you have dissolved the powder as described above, screw the enclosed syringe with its Luer-Lock connector onto the product vial with the transparent part of the transfer system. (7) This allows you to easily draw the dissolved drug into the syringe. A separate filter is not necessary because the transfer system has its own integral filter. • Carefully disconnect the vial with the transparent part of the transfer system from the syringe. Use the enclosed butterfly needle and administer immediately by slow intravenous injection. The injection rate must not exceed 2-3 ml/minute. • After the butterfly needle has been used, it can be made safe with the protective cap.|