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Drug Details

HAEMATE P

• Drug Class Description
  Factor VIII.
• Generic Name
  Factor VIII
• Presentation
  Powder and solvent for solution for injection or infusion
• Description
  Haemate P 500 Haemate P 500 is presented as a powder and solvent for solution for injection or infusion containing nominally 1200 International Units (IU) human plasma-derived von Willebrand Factor-ristocetin co-factor activity (VWF:RCo) and 500 IU human coagulation factor VIII activity (FVIII:C)per vial. Haemate P 500 contains approximately 120 IU/ml (1200 IU/10ml) human plasma-derived VWF:RCo when reconstituted with 10 ml water for injections. Haemate P 500 contains approximately 50 IU/ml (500 IU/10ml) human plasma-derived coagulation Factor VIII:C when reconstituted with 10 ml water for injections. Haemate P 1000 Haemate P 1000 is presented as a powder and solvent for solution for injection or infusion containing nominally 2400 International Units (IU) human plasma-derived von Willebrand Factor-ristocetin co-factor activity (VWF:RCo) and 1000 IU human coagulation factor VIII activity (FVIII:C)per vial. Haemate P 1000 contains approximately 160 IU/ml (2400 IU/10ml15ml) human plasma-derived VWF:RCo when reconstituted with 15 ml water for injections. Haemate P 1000 contains approximately 66.6 IU/ml (1000 IU/10ml15ml) human plasma-derived coagulation Factor VIII:C when reconstituted with 15 ml water for injections. The specific activity of Haemate P is approximately 3-17 IU VWF:RCo/mg protein. The factor VIII (FVIII) potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The specific activity of Haemate P is approximately 2-6 IU FVIII:C/mg protein.
• Indications
  von Willebrand Disease (VWD): Prophylaxis and treatment of haemorrhage or surgical bleeding, when desmopressin (DDAVP) treatment alone is ineffective or contra-indicated Haemophilia A (congenital factor VIII deficiency): Prophylaxis and treatment of bleeding This product may be used in the management of acquired factor VIII deficiency and for the treatment of patients with antibodies against factor VIII
• Adult Dosage
  

  Treatment of VWD and Haemophilia A should be supervised by a physician experienced in the treatment of haemostatic disorders.

  Posology

  von Willebrand Disease:

  Generally, 1 IU/kg VWF:RCo raises the circulating level of VWF:RCo by 0.02 IU/ml (2%).

  Levels of VWF:RCo greater than 0.6 IU/ml (60%) and of FVIII:C greater than 0.4 IU/ml (40%) should be achieved.

  Usually, 40-80 IU/kg bodyweight VWF:RCo and 20-40 IU/kg bodyweight FVIII:C are recommended to achieve haemostasis.

  An initial dose of 80 IU/kg VWF:RCo may be required, especially in patients with type 3 von Willebrand disease where maintenance of adequate levels may require higher doses than in other types of von Willebrand disease.

  Prevention of haemorrhage in case of surgery or severe trauma

  For prevention of excessive bleeding during or after surgery, the injection should be started 1 to 2 hours before the surgical procedure.

  An appropriate dose should be re-administered every 12 - 24 hours. The dose and duration of treatment will depend on the clinical status of the patient, the type and severity of bleeding and both the VWF:RCo and FVIII:C levels.

  When using a factor VIII-containing von Willebrand factor product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII:C. After 24 - 48 hours of treatment, in order to avoid an uncontrolled rise in FVIII:C, reduced doses and/or prolongation of the dose interval should be considered.

  Dosing in children is based on bodyweight and is therefore generally based on the same guidelines as for adults. The frequency of administration should always be tailored to clinical effectiveness in the individual case.

  Haemophilia A:

  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, which are related to the current World Health Organisation (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 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 FVIII:C is based on the empirical finding that 1 IU factor VIII:C per kg bodyweight raises the plasma factor VIII activity by about 2% of normal activity (2 IU/dl). The required dosage is determined using the following formula:

  Required units = body weight (kg) x desired factor VIII:C rise (% or IU/dl) x 0.5.

  The amount to be administered and the frequency of administration should always be tailored to clinical effectiveness in the individual case.

  In the case of the following haemorrhagic events, the factor VIII activity should not fall below the indicated plasma activity level (in % of normal or IU/dl) within the corresponding period.

  The following table can be used to guide dosing in bleeding episodes and surgery:

  Degree of haemorrhage / Type of surgical procedure	FVIII:C level required (% or IU/dl)	Frequency of Doses (hours) /Duration of therapy (days)
  >Haemorrhage
  Early haemarthrosis, muscle bleeding or oral bleeding	20 - 40	Repeat every 12 - 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 - 24 hours for 3 - 4 days or more until pain and disability are resolved.
  Life-threatening haemorrhages	60 - 100	Repeat infusion every 8 - 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 postoperative)	Repeat infusion every 8 - 24 hours until adequate wound healing, then treat for at least another 7 days to maintain a FVIII:C activity of 30 to 60% or IU/dl.

  During the course of treatment, appropriate determination of FVIII:C 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 FVIII:C 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 - 40 IU factor VIII:C per kg bodyweight at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

  Patients should be monitored for the development of factor VIII inhibitors. If the expected FVIII:C activity 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 be directed by physicians with experience in the care of patients with haemophilia.

  There are no data from clinical studies regarding the dosage of Haemate P in children with haemophilia A.

  Method of administration

  The preparation should be warmed to room or body temperature, then reconstituted as described in section 6.6. Then the product should be administered slowly via the intravenous route, at a rate comfortable for the patient.

  Where a large volume is required, infusion is an alternative option. The reconstituted preparation should be transferred to an approved infusion system.

  The injection or infusion rate should not exceed 4 ml per minute. The patient should be observed for any immediate reaction. Should any reaction occur which might be related to administration of Haemate P, the rate of infusion should be decreased or administration stopped, as appropriate.

• Child Dosage
  By intravenous infusion according to patient's weight, severity of haemorrhage and presence of inhibitors; see data sheet.
• Contra Indications
  

  Hypersensitivity to any of the constituents of Haemate P.

• Special Precautions
  

  As with any intravenous infusion of a plasma-derived protein, allergic type hypersensitivity reactions are possible. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. 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, the patient 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 implemented.

  Haemate P contains up to 140 mg sodium per 1000 IU. This should be taken into consideration for patients on a sodium-controlled diet.

  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 other non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal 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 products.

  It is strongly recommended that every time that Haemate P 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.

   

  von Willebrand Disease:

  There is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors. Therefore, patients at risk must be monitored for early signs of thrombosis. Prophylaxis against venous thromboembolism should be instituted, according to the current recommendations.

  When using a factor VIII-containing VWF product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII:C. In patients receiving FVIII-containing VWF products, plasma levels of FVIII:C should be monitored to avoid sustained excessive FVIII:C plasma levels which may increase the risk of thrombotic events, and anti-thrombotic measures should be considered.

  Patients with von Willebrand disease, especially type 3 patients, may develop neutralising antibodies (inhibitors) to VWF. If the expected VWF:RCo activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an appropriate assay should be performed to determine if a VWF inhibitor is present. In patients with high levels of inhibitor, VWF therapy may not be effective and other therapeutic options should be considered.

   

  Haemophilia A:

  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 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 inhibitory antibodies by appropriate clinical observations and laboratory tests. In patients with high levels of inhibitor, therapy may not be effective and other therapeutic options should be considered.

• Interactions
  

  No interactions of human coagulation factor VIII or von Willebrand factor products with other medicinal products are known.

• Adverse Drug Reactions
  

  The following adverse reactions are based on experience from clinical trials and on post-marketing experience. The following standard categories of frequency are used:

  Very common 1/10, Common 1/100 and 1/10, Uncommon 1/1000 and 1/100,
  Rare 1/10,000 and 1/1000, Very rare 1/10,000

  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 in very rare cases, and may in some cases progress to severe anaphylaxis (allergic shock).

  On rare occasions, fever has been observed.

  When very large or frequently repeated doses are needed, or when inhibitors are present or when pre-or post-surgical care is involved, all patients should be monitored for signs of hypervolaemia. In addition, those patients with blood groups A, B and AB should be monitored for signs of intravascular haemolysis and/or decreasing haematocrit values.

  Patients with von Willebrand disease, especially type 3 patients, may very rarely develop neutralising antibodies (inhibitors) to VWF. If such inhibitors occur, the condition will manifest itself as an inadequate clinical response. Such antibodies are precipitation and occur in close association with anaphylactic reactions. Therefore, patients experiencing anaphylactic reaction should be evaluated for the presence of an inhibitor.

  There is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors.

  In patients receiving factor VIII-containing von Willebrand factor products sustained excessive FVIII:C plasma levels may increase the risk of thrombotic events.

  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. The experience from clinical trials with Haemate P in previously untreated patients (PUPs) is very limited. Therefore, no valid figures on incidence of clinically relevant specific inhibitors can be provided. 

  In all such cases, it is recommended that a specialised haemophilia centre be contacted.