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Drug Details

Haemonine 500 / Haemonine 1000

• Presentation
  Powder and solvent for solution for injection.
• Description
  Human plasma derived coagulation factor IX; Haemonine® 500 / Haemonine® 1000 is presented as a powder and solvent for solution for injection containing either 500 or 1000 IU human coagulation factor IX per vial. When reconstituted with either 5 ml or 10 ml water for injections, Haemonine® 500 / Haemonine® 1000 contains approximately 100 IU/ml human coagulation factor IX. The potency (IU) is determined using the European Pharmacopoeia one stage clotting test. The specific activity of Haemonine® 500 / Haemonine® 1000 is 70 IU/mg protein.
• Indications
  

  Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).

• Adult Dosage
  

  Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia.

  Posology

  The dosage 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.

  The 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 dosage is determined using the following formula:

  Required units = body weight (kg) x desired factor IX rise (%) (IU/dl) x 0.8

  The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case. Factor IX products rarely require to be administered more than once daily.

  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)
  Haemorrhage
  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.
  Surgery
  Minor including tooth extraction	30 - 60	Every 24 hours, at least 1 day, until healing is achieved.
  Major	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).

  During 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. 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. Individual patients may vary in their response to factor IX, achieving different levels of in vivo recovery and demonstrating different half-lives.

  For long term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 20 to 30 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.

  There are insufficient data to recommend the use of Haemonine^® 500 / Haemonine^® 1000 in children less then 6 years of age. 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, F IX 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. 

  Method of administration

  Dissolve the preparation as described in Section 6.6. The product should be administered via the intravenous route. It is recommended to not exceed a maximal infusion rate of 5 ml/min.

• Contra Indications
  

  Hypersensitivity to the active substance, to any of the excipients or to heparin.

• Special Precautions
  

  As with any intravenous protein product, allergic type hypersensitivity reactions are possible. The product contains traces of human proteins other than factor IX. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If these symptoms occur, they should be advised to discontinue use of the product immediately and contact their physician. In case of shock, the current medical standards for shock-treatment should be observed.

  Standard 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 HIV, HBV and HCV, and for the non-enveloped 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.

  After 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 concentrates, 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.

  Since the use of factor IX complex concentrates has historically been associated with the development of thromboembolic complications, the risk being higher in low purity preparations, the use of factor IX-containing products may be potentially hazardous in patients with signs of fibrinolysis and in patients with disseminated intravascular coagulation (DIC). Because 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^® 500 / Haemonine^® 1000 should be weighed against the risk of these complications.

  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.

  It is strongly recommended that every time that Haemonine^® 500 / Haemonine^® 1000 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.

• Interactions
  

  No interactions of human coagulation factor IX products with other medicinal products are known.

• Adverse Drug Reactions
  

  • Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, fever, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently in patients treated with factor IX containing products. In some cases, these reactions have progressed to severe anaphylaxis, and they have occurred in close temporal association with development of factor IX inhibitors.

  • Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reaction.

  • On rare occasions fever has been observed.

  • 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 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.

  • 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.

  • Haemonine^® 500 / Haemonine^® 1000 may contain traces of heparin below the limit of quantitation (0.1 IU/ml) which may cause allergic 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.

  For the evaluation of undesirable reactions of Haemonine^®, the following frequencies were used:

  Very common:	1/10
  Common:	1/100 to <1/10
  Uncommon:	1/1,000 to <1/100
  Rare:	1/10,000 to <1/1,000
  Very rare:	<1/10,000

  The following adverse reactions have been reported from patients in clinical studies (1,493 exposure days):

  MedDRA Standard System Organ Class	Adverse reactions	Frequency
  General disorders and administration site conditions	Feeling cold	rare
  Respiratory, thoracic and mediastinal disorders	Dyspnoe	rare