Treatment and prevention of bleeding episodes in patients with hemophilia A (congenital FVIII deficiency).

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 World Health Organisation (WHO) international 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% to 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:

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, a 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.

A clinical study which was conducted in 15 patients of 6 years of age or less did not identify any special dosage requirements for children.

The use of OCTANATE in 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. See also 4.4.

Method of administration

Dissolve the preparation as described under 6.6. The product should be administered via the intravenous route. It is recommended not to administer more than 2 - 3 ml per minute.

·         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.

·         The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication of the treatment 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 inhibitory antibodies by appropriate clinical observations and laboratory test. See also 4.8. Undesirable effects

·         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.

·         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 (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. hemolytic 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.

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

Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and lactation only if clearly indicated.

No effects on ability to drive and use machines have been observed.

·         Hypersensitivity or allergic reactions (which may include angiooedema, 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. In such cases, it is recommended that a specialised haemophilia centre be contacted.

rare (>=1/10,000, <1/1,000)

very rare (<1/10,000), including isolated reports

·         For information on viral safety see 4.4.

To report any side effect(s):

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.

No case of overdose has been reported.

Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII

ATC-Code: B02BD02

The factor VIII/ von Willebrand factor complex consists of two molecules (FVIII and vWF) with different physiological functions. When infused into a haemophiliac patient, factor VIII binds to von Willebrand factor in the patient’s circulation.

Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed.

Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles, or internal organs, either spontaneously or as a results of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Human plasma coagulation factor VIII (from the concentrate) is a normal constituent of the human plasma and acts like the endogenous factor VIII. After injection of the product, approximately two-thirds to three-quarter of the factor VIII remain in the circulation. The level of factor VIII activity reached in the plasma should be between 80% - 120% of the predicted factor VIII activity.
Plasma factor VIII activity decreases by a two-phase exponential decay. In the initial phase, distribution between the intravascular and other compartments (body fluids) occurs with a half-life of elimination from the plasma of 3 to 6 hours. In the subsequent slower phase (which probably reflects the consumption of factor VIII), the half-life varies between 8 to 20 hours, with an average of 12 hours. This corresponds to the true biological half-life.

For OCTANATE the following results were achieved for two pharmacokinetic studies with 10 and 14 haemophilia A patients, respectively:

AUC*  = area under the curve,

MRT*  = mean residence time,

SD*  = standard deviation

Toxicological data available on tri-n-butylphosphate (TNBP) and polysorbate 80 (tween 80), the solvent/detergent reagents used in the SD method of viral inactivation during manufacture of OCTANATE, although limited for the latter, indicate that adverse effects are unlikely at the anticipated human exposures.

Even doses of several times the recommended human dosage per kilogram body weight of these reagents show no toxic effects on laboratory animals. No mutagenic potential was observed for either of the two substances.

Powder:      - Sodium citrate
                   - Sodium chloride
                   - Calcium chloride
                   - Glycine

Solvent:      -Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Only the provided injection or infusion sets should be used, because treatment failure can occur as a consequence of human coagulation factor VIII adsorption to the internal surface of some injection/infusion equipment.

Store at 2°C - 8°C.

Do not freeze.

Keep the vials in the outer carton in order to protect from light.

For storage conditions of the reconstituted medicinal product, see section 6.3.

Powder in a vial (type I glass), with a stopper (halobutyl rubber), and a flip off cap; solvent in a vial (type I glass), with a stopper (halobutyl rubber), and a flip off cap; one disposable syringe, one double ended needle, one filter needle, one injection needle, and two alcohol swabs.

The available pack sizes differ in the amount of human blood coagulation factor VIII/ solvent:

OCTANATE 250 IU: reconstitution with 5 ml of solvent

OCTANATE 500 IU: reconstitution with 10 ml of solvent

OCTANATE 1000 IU: reconstitution with 10 ml of solvent

Not all pack sizes may be marketed.

Please read all the instructions and follow them carefully!

During the procedure described below, sterility must be maintained!

Instructions for reconstitution:

1. Allow the solvent (Water for Injections) and the concentrate in the closed vials to reach room temperature. This temperature should be maintained during reconstitution.
If a water bath is used for warming, care must be taken to avoid water coming into contact with the rubber stoppers or the caps of the vials. The temperature of the water bath should not exceed 37°C.

2. Remove the caps from the concentrate vial and the water vial and clean the rubber stoppers with an alcohol swab.

3. Remove the protective cover from the short end of the double-ended needle, making sure not to touch the exposed tip of the needle.
Then perforate the centre of the water vial rubber stopper with the vertically held needle.
In order to withdraw the fluid from the water vial completely, the needle must be introduced into the rubber stopper in such a way that it just penetrates the stopper and is visible in the vial.

4. Remove the protective cover from the other, long end of the double-ended needle, making sure not to touch the exposed tip of the needle.
Hold the water vial upside-down above the upright concentrate vial and quickly perforate the centre of the concentrate vial rubber stopper with the needle. The vacuum inside the concentrate vial draws in the water.

5. Remove the double-ended needle with the empty water vial from the concentrate vial, then slowly rotate the vial until the concentrate is completely dissolved. Octanate dissolves quickly at room temperature to a clear solution. The reconstitution time is less than 10 minutes at room temperature.

After reconstitution with the supplied solvent, Octanate is administered intravenously. The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. Reconstituted products should be inspected visually for particulate matter and discoloration prior to administration.
The reconstituted solution must be used immediately and on one occasion only.

Instructions for injection:

As a precautionary measure, the patients pulse rate should be measured before and during the factor VIII injection. If a marked increase in the pulse rate occurs the injection speed must be reduced or the administration must be interrupted.

1. After the concentrate has been reconstituted in the manner described above, remove the protective cover from the filter needle and perforate the rubber stopper of the concentrate vial.

2. Remove the cap of the filter needle and attach the syringe.

3. Turn the vial with the attached syringe upside-down and draw the solution up into the syringe.

4. Disinfect the intended injection site with an alcohol swab.

5. Remove the filter needle from the syringe and attach the injection needle to the syringe instead.

6. Inject the solution intravenously at a slow speed of 2 - 3 ml per minute.

Patients using more than one vial of OCTANATE concentrate may use the same injection needle and syringe, but the filter needle is for single use only. Always use a filter needle when drawing up the preparation into a syringe.

Any unused product or waste material should be disposed of in accordance with local requirements.