• OCTANATE 100 IU/ml is presented as a powder and solvent for solution for injection containing nominally 1000 IU human coagulation factor VIII per vial. The product contains approximately 100 IU/ml human coagulation factor VIII when reconstituted with 10 ml of Water for Injections. The potency (IU) is determined using the European Pharmacopoeia chromogenic assay against the World Health Organisation (WHO) international standard. The specific activity of OCTANATE is 100 IU/ mg protein. The product contains 60 IU/ml von Willebrand Factor (VWF:RCo).

Powder and solvent for solution for injection.

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.

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 IU factor VIII per kg body weight raises the plasma factor VIII activity by 1.5 %-2 % of normal. The required dosage is determined using the following formula:

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

The amount and frequency of administration should always be adjusted according to the clinical effectiveness in the individual patient.

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 disability are resolved.
Life-threatening haemorrhages	60 - 100	Repeat infusion every 8 to 24 hours until threat is resolved.
Surgery
Minorincluding 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 to 24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a FVIII activity of 30% to 60%.

For long-term prophylaxis against bleeding in patients with severe haemophilia A, doses of 20 to 40 IU of factor VIII per kg body weight should be given at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter application intervals or higher doses may be necessary.

The use of OCTANATE on previously untreated patients (PUPs) has not been established in controlled clinical trials, the antibody development of these patients should be analysed with an appropriate test (Bethesda test). There are insufficient data to recommend the use of OCTANATE in previously untreated patients (PUPs).

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 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 per minute.

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

• 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, standard medical treatment of shock should be implemented.

• There have been reports in the literature showing a relationship between the occurrence of a factor VIII inhibitor and allergic reactions. Therefore, if allergic reactions occur, the patient should be examined for the presence of an inhibitor. Patients with factor VIII inhibitors may be at an increased risk of anaphylaxis with subsequent treatment with factor VIII. Consequently, the first administration of factor VIII should, according to the treating physician's judgement, be performed under medical supervision where appropriate medical care for allergic reactions can be provided.

• The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication of the treatment of individuals with haemophilia A. These inhibitors are 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 related to the exposure to 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 test. See also 4.8. Undesirable effects.

• 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.

• It is strongly recommended that every time OCTANATE is administered, 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.

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

• 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, chest tightness, 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 antibodies (inhibitors) to factor VIII. If such inhibitors occur, the condition will manifest as an insufficient clinical response. Treatment of such patients requires the expertise of a specialised haemophilia centre.

Octapharma Limited

30 June 2009