Optivate^®, 100 IU/mL human factor VIII, a powder for solution.

Optivate is a concentrate of human coagulation factor VIII with associated von Willebrand factor (VWF) (the natural stabiliser for FVIII). There are no added proteins as stabilisers. The product is obtained from blood from screened donors. These donors are selected from the USA.

Each vial contains nominally 250 IU, 500 IU or 1000 IU of human coagulation factor VIII. One mL of Optivate contains approximately 100 IU of human coagulation factor VIII after reconstitution with 2.5 mL (250 IU), 5 mL (500 IU) or 10 mL (1000 IU) of Sterilised Water for Injections, Ph.Eur..

The factor VIII potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The specific activity of Optivate is approximately 800 IU/mg protein when VWF is discounted and approximately 43 IU/mg protein when the presence of VWF is considered in the calculation.

The product contains approximately 172 IU VWF:RCo per mL when reconstituted with Sterilised Water for Injections as described above.

The specific activity of Optivate is approximately 75 IU of VWF:RCo/mg protein.

The VWF potency (IU) is measured according to ristocetin cofactor activity (VWF:RCo) compared to the International Standard for von Willebrand factor concentrate (WHO).

The label on each vial states the assayed amounts of factor VIII and VWF ristocetin cofactor activities.

For a full list of excipients, see 6.1.

Powder for solution.

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

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

The dosage and duration of the substitution therapy depend on the severity of the FVIII deficiency, on the location and extent of the bleeding and the patient's clinical condition.

Posology

On demand treatment

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 2.2% - 2.7% of normal activity (2.2-2.7 IU/dL). The required dosage is determined using the following formula:

The amount to be administered and the frequency of administration should always be orientated 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; IU/dL) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:

Prophylaxis

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.

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.

Paediatric patients

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 in 6.6. The product should be administered via the intravenous route at a rate not exceeding 3 mL per minute (note that increasing the rate of administration may result in side effects).

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 and VWF. 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 for shock should be implemented.

Standard measures are implemented 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 non-enveloped viruses HAV and parvovirus B19.

It is strongly recommended that every time that Optivate 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.

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.

Cases of recurrent inhibitor (low titre) have been observed after switching from one FVIII product to another in previously treated patients with more than 100 exposure days who have a previous history of inhibitor development. Therefore, it is recommended to monitor patients carefully for inhibitor occurrence following any product switch.

In general, all patients treated with human coagulation factor VIII should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests.

See also 4.8 Undesirable effects.

No interactions of human coagulation factor VIII products with other medicinal products have been reported.

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.

Optivate has no influence on the ability to drive and use machines.

The following adverse reactions have been reported from 96 patients in clinical studies. Approximately 10% of patients can be expected to experience adverse reactions on long-term treatment. Frequencies are defined as: 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).

In post-marketing experience, the following additional undesirable effects have been reported: sneezing, cough, throat irritation, abdominal pain and malaise.

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.

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. One previously untreated patient (PUP) has been treated in the clinical development programme. Neither he nor any of the 95 previously treated patients (PTPs) in the clinical trials has developed inhibitors. The median number of exposure days in these patients was 97 days (range 2 to 408 days).

For information on viral safety see 4.4.

No case of overdose has been reported.

Pharmacotherapeutic Group :

Antihaemorrhagics: blood coagulation factor VIII, ATC code: B02BD02.

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) 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 result 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.

In addition to its role as a factor VIII protecting protein, von Willebrand factor mediates platelet adhesion to sites of vascular injury and plays a role in platelet aggregation.

From clinical trial experience, young children using prophylactic Optivate experienced less bleeds than those only using it on demand. For doses in children see 4.2.

The pharmacokinetics of Optivate have been evaluated in 15 patients with severe haemophilia A after bolus doses of 50 IU/kg. The mean results were as follows:

During the clinical trials, there were 309 assessments of incremental recovery, all based on the maximum FVIII:C in the first hour (ISTH 2001). These assessments have involved 27 batches of Optivate and 70 adults with severe haemophilia A. The overall values of incremental recovery were as follows:

The factor VIII and von Willebrand factor in Optivate are normal constituents of human plasma and act in the same way as the endogenous proteins. Therefore, safety testing is not relevant.

However, an acute toxicity study and a repeated dose toxicity study in mice indicated that the Optivate formulation was not toxic, even at levels up to 20 times that likely to be used in man. In these studies, the various constituents of the product were administered to the test animals in different, greater, amounts for each excipient, compared to that in a clinical dose.

It is scientifically inappropriate to conduct genotoxicity or carcinogenicity studies with plasma coagulation factor VIII with or without its natural stabiliser, VWF.

The reconstituted solution contains:

Sodium chloride

Sodium citrate

Calcium chloride

Polysorbate 20

Trehalose.

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

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

Unopened (at 2°C - 25°C, in the dark) 3 years.

Store below 25°C. Do not freeze. Protect from light.

The product is presented as a 250 IU, 500 IU or 1000 IU presentation in Type I, Ph.Eur., glass vials. These vials are stoppered with a halobutyl rubber freeze-drying stopper under vacuum and then oversealed with a snap-off polypropylene cap and aluminium lacquered skirt.

Supplied with the product is a Transfer Device called Mix2Vial^TM to allow needle-free, easy and safe reconstitution of the product with the Sterilised Water for Injection, (Ph.Eur.).

An Administration User Kit can be provided upon request from Bio Products Laboratory, which will include:

Alcohol swabs: one is used to clean the vial stoppers after flipping off the caps. The other should be used to disinfect the skin at the injection site.

Winged Infusion set: a butterfly No. 23 needle for administration of the product.

20 mL syringe: the dissolved solution is withdrawn into the syringe. This size of syringe is provided to enable more than one vial to be administered using one syringe (see Step 6 of the diagram).

Plaster: to stick on the injection site after administration.

Optivate should only be reconstituted with Water for Injections provided with the product. The 250 IU, 500 IU and 1000 IU presentations should be reconstituted using 2.5 mL, 5 mL and 10 mL Sterilised Water for Injections, Ph.Eur., respectively.

The container of Optivate and Water for Injections should be brought to between 20°C and 30°C prior to the removal of the flip-off closure from the product vial.

The Mix2Vial^TM Transfer Device is provided with the product for needle-free, easy and safe use.

The reconstitution is performed as follows:

Note: If you have more than one vial to make up your dose, repeat Steps 1 through 6 withdrawing the solution in the vial into the same syringe.

The Transfer Device supplied with the product is sterile and cannot be used more than once. When the reconstitution process is complete, dispose of in the 'sharps box'.

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

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 discolouration prior to administration. Infuse the product as soon as possible after reconstitution and certainly within one hour.

BPL, Bio Products Laboratory

Dagger Lane, Elstree, Herts, WD6 3BX

United Kingdom

Tel: +44 (0) 208 258 2200

Email: info@bpl.co.uk

PL08801/0051

December 2004

November 2009                                      Item code: OptSmPC5