Helixate NexGen 250/500/1000/2000/3000 IU powder and solvent for solution for injection.

2.1 General description

Each vial contains nominally 250/500/1000/2000/3000 IU human coagulation factor VIII (octocog alfa).

Human coagulation factor VIII is produced by recombinant DNA technology (rDNA) in baby hamster kidney cells containing the human factor VIII gene.

2.2 Qualitative and quantitative composition

Helixate NexGen 250/500/1000 IU:

One ml of Helixate NexGen contains approximately 100/200/400 IU (250/500/1000 IU / 2.5 ml) of human coagulation factor VIII (octocog alfa) after reconstitution.

Helixate NexGen 2000 IU:

One ml of Helixate NexGen contains approximately 400 IU (2000 IU / 5.0 ml) of human coagulation factor VIII (octocog alfa) after reconstitution.

Helixate NexGen 3000 IU:

One ml of Helixate NexGen 3000 IU contains approximately 600 IU (3000 IU / 5.0 ml) of human coagulation factor VIII (octocog alfa) after reconstitution.

The potency (IU) is determined using the one-stage clotting assay against the FDA Mega standard which was calibrated against WHO standard in International Units (IU).

The specific activity of Helixate NexGen is approximately 4000 IU/mg protein.

Solvent: water for injections.

For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Powder: dry white to slightly yellow powder or cake.

Solvent: water for injection, a clear and colourless solution.

The reconstituted medicinal product is a clear and colourless solution.

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

This preparation does not contain von Willebrand factor 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 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 the 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 dose 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 1.5% to 2.5% of normal activity. The required dose is determined using the following formulae:

I. Required IU = body weight (kg) × desired factor VIII rise (% of normal) × 0.5

On demand treatment

The dose, frequency and duration of the substitution therapy must be individualised according to the patient's needs (weight, severity of disorder of the haemostatic function, the site and extent of the bleeding, the presence of inhibitors, and the factor VIII level desired).

The following table provides a guide for factor VIII minimum blood levels. In the case of the haemorrhagic events listed, the factor VIII activity should not fall below the given level (in % of normal) in the corresponding period:

The amount to be administered and the frequency of administration should always be adapted according to the clinical effectiveness in the individual case. Under certain circumstances larger amounts than those calculated may be required, especially in the case of the initial dose.

During the course of treatment, appropriate determination of factor VIII levels is advised in order to guide the dose to be administered and the frequency at which to repeat the 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.

Continuous infusion

It has been shown in a clinical study performed with adult haemophilia A patients who undergo a major surgery that Helixate NexGen can be used for continuous infusion in surgeries (pre-, during and postoperative). In this study heparin was used to prevent thrombophlebitis at the infusion site as with any other long term intravenous infusions. For the calculation of the initial infusion rate, clearance can be obtained by performing a pre-surgery decay curve, or by starting from an average population value (3.0-3.5 ml/h/kg) and then adjust accordingly.

Infusion rate (in IU/kg/h) = Clearance (in ml/h/kg) × desired factor VIII level (in IU/ml)

For continuous infusion, clinical and in vitro stability has been demonstrated using ambulatory pumps with a PVC reservoir. Helixate NexGen contains low level of polysorbate-80 as an excipient, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC) materials. This should be considered for a continuous infusion administration.

Prophylaxis

For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 IU of Helixate NexGen per kg body weight at intervals of 2 to 3 days.

In some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary.

Paediatric population

Data have been obtained from clinical studies in 61 children under 6 years of age and non-interventional studies in children of all ages.

Patients with inhibitors

Patients should be monitored for the development of factor VIII inhibitors. If the expected plasma factor VIII 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. If the inhibitor is present at levels less than 10 Bethesda Units (BU) per ml, administration of additional recombinant coagulation factor VIII may neutralise the inhibitor and permit continued clinically effective therapy with Helixate NexGen. However, in the presence of an inhibitor the doses required are variable and must be adjusted according to clinical response and monitoring of plasma factor VIII activity. In patients with inhibitor titres above 10 BU or with high anamnestic response, the use of (activated) prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) preparations has to be considered. These therapies should be directed by physicians with experience in the care of patients with haemophilia.

Method of administration

For intravenous use.

Helixate NexGen should be injected intravenously over several minutes. The rate of administration should be determined by the patient's comfort level (maximal rate of infusion: 2 ml/min).

Continuous infusion

Helixate NexGen can be infused by continuous infusion. The infusion rate should be calculated based on the clearance and the desired FVIII level.

Example: for a 75 kg patient with a clearance of 3 ml/h/kg, the initial infusion rate would be 3 IU/h/kg to achieve a FVIII level of 100%. For calculation of ml/hour, multiply infusion rate in IU/h/kg by kg bw/concentration of solution (IU/ml).

Example for calculation of infusion rate for continuous infusion after initial bolus injection

Higher infusion rates may be required in conditions with accelerated clearance during major bleedings or extensive tissue damage during surgical interventions.

After the initial 24 hours of continuous infusion, the clearance should be recalculated every day using the steady state equation with the measured FVIII level and the rate of infusion using the following equation: clearance = infusion rate/actual FVIII level.

During continuous infusion, infusion bags should be changed every 24 hours.

For instructions on reconstitution of the medicinal product before administration, see section 6.6 and the package leaflet.

- Known hypersensitivity to the active substance or to any of the excipients.

- Known allergic reactions to mouse or hamster protein.

Hypersensitivity reactions

As with any intravenous protein product, allergic type hypersensitivity reactions are possible.

Patients should be made aware that the potential occurrence of chest tightness, dizziness, mild hypotension and nausea during infusion can constitute an early warning for hypersensitivity and anaphylactic reactions. Symptomatic treatment and therapy for hypersensitivity should be instituted as appropriate. If allergic or anaphylactic reactions occur, the injection/infusion should be stopped immediately and patients should contact their physician. In case of shock, the current medical standards for shock treatment should be observed.

Antibodies (inhibitors)

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 Modified Bethesda Units (BU) per ml of plasma. The risk of developing inhibitors is correlated to the exposure to anti-haemophilic factor VIII and to genetic factors among others, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.

Cases of recurrence of inhibitors (low titre) have been observed after switching from one recombinant factor VIII product to another in previously treated patients with more than 100 exposure days who have a history of inhibitor development.

Patients treated with recombinant coagulation factor VIII should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. (See also section 4.8).

Continuous infusion

In a clinical study about the use of continuous infusion in surgeries, heparin was used to prevent thrombophlebitis at the infusion site as with any other long term intravenous infusions.

Registration

In the interest of the patients, it is recommended that, whenever possible, every time that Helixate NexGen is administered to them, the name and the batch number of the product is registered.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially “sodium free”.

No interactions of Helixate NexGen with other medicinal products are known.

Animal reproduction studies have not been conducted with Helixate NexGen.

Based on the rare occurrence of haemophilia A in women, experience regarding the use of Helixate NexGen during pregnancy and breast-feeding is not available. Therefore, Helixate NexGen should be used during pregnancy and breast-feeding only if clearly indicated.

There are no fertility data available.

Helixate NexGen has no influence on the ability to drive or to use machines.

The most commonly reported adverse drug reaction occurring is the formation of neutralising antibodies (prevalent in previously untreated or minimally treated patients).

The frequencies of adverse reactions reported with Helixate NexGen are summarized in the table below. Within each frequency group, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100), and rare ( 1/10,000 to < 1/1,000).

* see section below

Description of selected adverse reactions

The formation of neutralising antibodies to factor VIII (inhibitors) is a known complication in the management of individuals with haemophilia A. In studies with recombinant factor VIII preparations, development of inhibitors is predominantly observed in previously untreated haemophiliacs. Patients should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests.

In clinical studies, Helixate NexGen has been used in the treatment of bleeding episodes in 37 previously untreated patients (PUPs) and 23 minimally treated pediatric patients (MTPs, defined as having equal to or less than 4 exposure days). Five out of 37 (14%) PUP and 4 out of 23 (17%) MTP patients treated with Helixate NexGen developed inhibitors: Overall, 9 out of 60 (15%) developed inhibitors, 6 out of 60 (10%) with a titre above 10 BU and 3 out of 60 (5%) with a titre below 10 BU. The median number of exposure days at the time of inhibitor detection in these patients was 9 days (range 3 - 18 days).

The median number of exposure days in the clinical studies was 114 (range: 4-478). Four of the five patients, who had not achieved 20 exposure days at the end of the study, ultimately achieved more than 20 exposure days in post-study follow-up and one of them developed a low titre inhibitor. The fifth patient was lost to follow-up.

In clinical studies with 73 previously treated patients (PTP, defined as having more than 100 exposure days), followed over four years, no de-novo inhibitors were observed.

In extensive post-registration studies with Helixate NexGen, involving more than 1000 patients the following was observed: Less than 0.2% PTP developed de-novo inhibitors. In a subset defined as having less than 20 exposure days at study entry, less than 11% developed de-novo inhibitors.

During studies, no patient developed clinically relevant antibody titres against the trace amounts of mouse protein and hamster protein present in the preparation. However, the possibility of allergic reactions to constituents, e.g. trace amounts of mouse and hamster protein in the preparation exists in certain predisposed patients (see sections 4.3 and 4.4).

No cases of overdose with recombinant coagulation factor VIII have been reported.

Pharmacotherapeutic group: Antihaemorrhagics: blood coagulation factor VIII, ATC code B02B D02.

The factor VIII/von Willebrand factor (vWF) complex consists of two molecules (factor VIII and vWF) with different physiological functions. When infused into a haemophilic patient, factor VIII binds to vWF 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.

Determination of activated partial thromboplastin time (aPTT) is a conventional in vitro assay method for biological activity of factor VIII. The aPTT is prolonged in all haemophiliacs. The degree and duration of aPTT normalisation observed after administration of Helixate NexGen is similar to that achieved with plasma-derived factor VIII.

The analysis of all recorded in vivo recoveries in previously treated patients demonstrated a mean rise of 2 % per IU/kg body weight for Helixate NexGen. This result is similar to the reported values for factor VIII derived from human plasma.

After administration of Helixate NexGen, peak factor VIII activity decreased by a two-phase exponential decay with a mean terminal half-life of about 15 hours. This is similar to that of plasma-derived factor VIII which has a mean terminal half-life of approx. 13 hours. Additional pharmacokinetic parameters for Helixate NexGen for bolus injection are: mean residence time [MRT (0-48)] of about 22 hours and clearance of about 160 ml/h. Mean baseline clearance for 14 adult patients undergoing major surgeries with continuous infusion are 188 ml/h corresponding to 3.0 ml/h/kg (range 1.6-4.6 ml/h/kg).

Even doses several fold higher than the recommended clinical dose (related to body weight) failed to demonstrate any acute or subacute toxic effects for Helixate NexGen in laboratory animals (mouse, rat, rabbit, and dog).

Specific studies with repeated administration such as reproduction toxicity, chronic toxicity, and carcinogenicity were not performed with octocog alfa due to the immune response to heterologous proteins in all non-human mammalian species.

No studies were performed on the mutagenic potential of Helixate NexGen, since no mutagenic potential could be detected in vitro or in vivo for the predecessor product of Helixate NexGen.

Powder

Glycine

Sodium chloride

Calcium chloride

Histidine

Polysorbate 80

Sucrose

Solvent

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Only the provided administration sets can be used because treatment failure can occur as a consequence of human recombinant coagulation factor VIII adsorption to the internal surfaces of some infusion equipment.

Helixate NexGen 250/500/1000/2000 IU:

30 months

Helixate NexGen 3000 IU:

24 months.

After reconstitution, the product should be used immediately. However, during in vitro studies, the chemical and physical in-use stability has been demonstrated for 24 hours at 30°C in PVC bags for continuous infusion.

Do not refrigerate after reconstitution.

Store in a refrigerator (2°C – 8°C). Do not freeze.

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

The product when kept in its outer carton may be stored at ambient room temperature (up to 25°C) for a limited period of 12 months.

In this case, the product expires at the end of this 12-month period; the new expiry date must be noted on the top of the outer carton.

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

Each package of Helixate NexGen contains:

• one vial with powder (10 ml clear glass type 1 vial with latex-free grey halogenobutyl rubber blend stopper and aluminium seal)

• one vial with solvent (6 ml clear glass type 1 vial with latex-free grey chlorobutyl rubber blend stopper and aluminium seal)

• an additional package with:

- 1 filter transfer device 20/20 (Mix2Vial)

- 1 venipuncture set

- 1 disposable 5 ml syringe

- 2 sterile alcohol swabs for single use

Detailed instructions for preparation and administration are contained in the package leaflet provided with Helixate NexGen.

Helixate NexGen powder should only be reconstituted with the supplied solvent (2.5 or 5.0 ml water for injections) using the supplied sterile Mix2Vial filter transfer device. Reconstitution should be performed in accordance with good practices rules, particularly with attention to asepsis. Gently rotate the vial until all powder is dissolved. After reconstitution the solution is clear. Do not use Helixate NexGen if you notice visible particulate matter or turbidity.

After reconstitution, the solution is drawn through the Mix2Vial filter transfer device into the sterile disposable syringe (both supplied).

Use the provided venipuncture set for intravenous injection.

For continuous infusion, the product must be prepared under aseptic conditions.

For single use only. Any unused solution must be discarded.

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

Bayer Pharma AG

13342 Berlin

Germany

Helixate NexGen 250 IU: EU/1/00/144/001

Helixate NexGen 500 IU: EU/1/00/144/002

Helixate NexGen 1000 IU: EU/1/00/144/003

Helixate NexGen 2000 IU: EU/1/00/144/004

Helixate NexGen 3000 IU: EU/1/00/144/005

250, 500, 1000 IU:

Date of first authorisation: 04 August 2000

Date of latest renewal: 06 August 2010

2000 IU:

Date of first authorisation: 18 December 2007

Date of latest renewal: 06 August 2010

3000 IU:

Date of first authorisation: 06 August 2010

22 August 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu