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Drug Details

Haemoctin 250 / Haemoctin 500

• Presentation
  Powder and solvent for solution for injection.
• Description
  One vial of Haemoctin® 250 / Haemoctin® 500 contains 250 IU / 500 IU human plasma derived coagulation factor VIII. When reconstituted with either 5 ml or 10 ml of water for injections, Haemoctin® 250 / Haemoctin® 500 contains approximately 50 IU/ml human coagulation factor VIII. The potency (IU) is determined using the European Pharmacopoeia chromogenic factor VIII coagulation assay. The specific activity of Haemoctin® 250 / Haemoctin® 500 is approximately 100 IU/mg protein
• Indications
  

  Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).

  This preparation does not contain von Willebrand factor in pharmacologically effective quantities and is therefore not indicated in von Willebrand´s disease.

• 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 VIII deficiency, on the location and extent of the bleeding and on the patient´s clinical condition.

  The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current WHO standard for factor VIII products. Factor VIII 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 VIII in plasma).

  One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage of factor VIII is based on the empirical finding that 1 International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by 1 % to 2 % of normal activity.

  The required dosage is determined using the following formula:

   

  Required units = body weight (kg) x desired factor VIII rise (%) x 0.5

  The 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 VIII activity should not fall below the given plasma activity level (in % of normal) 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 VIII level required (%)	Frequency of doses (hours)/Duration of therapy (days)
  Haemorrhage
  Early haemarthrosis, muscle bleeding or oral bleeding	20 - 40	Repeat every 12 to 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 12 to 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 VIII activity of 30 - 60%.

  During the course of treatment, appropriate determination of factor VIII 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 VIII activity) is indispensable. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives.

  For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 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 Haemoctin^® 250 / Haemoctin^® 500 in children less then 6 years of age.

  Patients should be monitored for the development of factor VIII inhibitors. If the expected factor VIII 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 VIII inhibitor is present. In patients with high levels of inhibitor factor VIII therapy may not be effective, and other therapeutic options should be considered.

  Management of such patients should only be directed by physicians with experience in the care of patients with haemophilia.

  Method of administration

  The product should be administered via the intravenous route. It is recommended not to administer more than 2 3 ml/min of Haemoctin^® 250 / Haemoctin^® 500.

• Contra Indications
  

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

• Special Precautions
  

  As with any intravenous protein product, allergic type hypersensitivity reactions are possible. The product contains traces of human proteins other than factor VIII. 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 VIII products.

  The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per ml of plasma using the modified assay. The risk of developing inhibitors is correlated to the exposure to anti-haemophilic factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days. Patients treated with human coagulation factor VIII should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory test. See also 4.8. Undesirable effects.

  It is strongly recommended that every time that Haemoctin^® 250 / Haemoctin^® 500 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.

  This medicinal product contains a maximum of 3.3 mmol sodium per standard dose of 2000 IU. To be taken into consideration by patients on a controlled sodium diet.

• Interactions
  

  No interactions of human coagulation factor VIII 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, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently, and may in some cases progress to severe anaphylaxis (including shock). On rare occasions, fever has been observed.

  Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor VIII. 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.

  From introduction in the market until January 2006 a total of about 500 000 standard dosages of Haemoctin^® 250, 500 and 1000 were applied. In total 12 cases of suspected development of inhibitors were received from clinical trials, spontaneous reporting and non interventional studies. This corresponds to a reporting frequency of 1 case on 40 864 applications.

  • 6 of these cases concern transient inhibitors.

  • In 9 cases the titres of inhibitors were below 10 BU and in 3 cases higher than 10 BU.

  • 5 cases concern inhibitor development in previously treated patients (PTPs), 3 cases concern inhibitor development in previously untreated patients (PUPs), 1 case concerned a minimally pretreated patient (16 ED) and in 3 cases exposure days were not reported.

  • 4 cases concern children under 6 years of age, in three of these cases the inhibitors were transient.

  For the evaluation of undesirable effects 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, including isolated reports

  From clinical trials, non interventional studies, spontaneous reporting and regular literature screening the following adverse reactions were reported on Haemoctin^® 250, 500 and 1000: 

  MedDRA Standard System Organ Class	Adverse reactions	Frequency
  Nervous system disorders	Haemorrhage brain	very rare
  Blood and lymphatic system disorders	Anaemia	very rare
  Skin and subcutaneous tissue disorders	Exanthema, urticaria, erythema	very rare
  Investigations	Anti factor VIII antibody positive	very rare

  No cases of transmission of infective agents have been confirmed so far.