Helixate NexGen

Helixate NexGen 250 IU powder and solvent for solution for injection

Helixate NexGen 500 IU powder and solvent for solution for injection

Helixate NexGen 1000 IU powder and solvent for solution for injection

Helixate NexGen 2000 IU powder and solvent for solution for injection

Helixate NexGen 3000 IU powder and solvent for solution for injection

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

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

- One mL Helixate NexGen 250 IU contains approximately 100 IU (250 IU / 2.5 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water for injections.

- One mL Helixate NexGen 500 IU contains approximately 200 IU (500 IU / 2.5 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water for injections.

- One mL Helixate NexGen 1000 IU contains approximately 400 IU (1000 IU / 2.5 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water for injections.

- One mL Helixate NexGen 2000 IU contains approximately 400 IU (2000 IU / 5 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water for injections.

- One mL Helixate NexGen 3000 IU contains approximately 600 IU (3000 IU / 5 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water for injections.

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.

Powder and solvent for solution for injection.

Powder: dry white to slightly yellow powder or cake.

Solvent: water for injection, a clear, 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.

This product is indicated for adults, adolescents and children of all ages.

Treatment should be 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.

On demand treatment

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

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:

Table 1: Guide for dosing in bleeding episodes and surgery

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, demonstrating different half-lives and recoveries.

Continuous infusion

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.

Special populations

Paediatric population

The safety and efficacy of Helixate NexGen in children of all ages have been established. 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

Intravenous use.

Helixate NexGen should be injected intravenously over 2 to 5 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).

Table 2: 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.

- Known allergic reactions to mouse or hamster protein.

Hypersensitivity

Allergic type hypersensitivity reactions are possible with Helixate NexGen. The product contains traces of mouse and hamster proteins and human proteins other than factor VIII.

If symptoms of hypersensitivity occur, patients should be advised to discontinue the use of the medicinal product immediately and contact their physician.

Patients should be informed of the early signs of hypersensitivity reactions including hives, nausea, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.

In case of shock, standard medical treatment for shock should be implemented.

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 Bethesda Units (BU) per mL of plasma using the modified assay. The risk of developing inhibitors is correlated to the exposure to 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 factor VIII product to another in previously treated patients with more than 100 exposure days who have a history of inhibitor development. Therefore, it is recommended to monitor all patients carefully for inhibitor occurrence following any product switch.

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

If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for the presence of factor VIII inhibitor should be performed. 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 haemophilia and factor VIII inhibitors.

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.

Sodium content

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

Cardiovascular events

Haemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-haemophilic patients when clotting has been normalised by treatment with FVIII. Elevation of FVIII levels following administration, in particular with existing cardiovascular risk factors, might put a patient into the same risk for vessel closure or myocardial infarction as for the non-haemophilic population. Consequently, patients should be evaluated and monitored for cardiac risk factors.

Catheter-related complications

If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteremia and catheter site thrombosis should be considered.

Documentation

It is strongly recommended that every time that Helixate NexGen 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 medicinal product.

Paediatric population

The listed warnings and precautions apply both to adults and children.

No interactions of Helixate NexGen with other medicinal products have been reported.

Animal reproduction studies have not been conducted with Helixate NexGen.

Pregnancy and breast-feeding

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.

Fertility

There are no fertility data available.

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

Summary of the safety profile

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 with recombinant factor VIII products and may in some cases progress to severe anaphylaxis (including shock). In particular the skin related reactions may occur commonly, whereas a progress to severe anaphylaxis (including shock) is considered to be rare.

Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor VIII. The condition may manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).

Frequencies have been evaluated according to the following convention: 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), not known (cannot be estimated from the available data).

Table 3: Frequency of adverse drug reactions

PUPs = previously untreated patients

PTPs = previously treated patients

MTPs = minimally treated patients

* see section below

Description of selected adverse reactions

Inhibitor development

Inhibitor development in previously untreated and treated patients (PUPs / PTPs) has been reported.

In clinical studies, Helixate NexGen has been used in the treatment of bleeding episodes in 37 previously untreated patients (PUPs) and 23 minimally treated paediatric patients (MTPs, defined as having ≤4 exposure days) with residual FVIII:C < 2 IU/dl. Five out of 37 (14%) PUP and 4 out of 23 (17%) MTP patients treated with Helixate NexGen developed inhibitors within 20 exposure days. Overall, 9 out of 60 (15%) developed inhibitors. One patient was lost to follow up and one patient developed a low-titre inhibitor during post study follow-up.

In one observational study, the incidence of inhibitor development in previously untreated patients with severe haemophilia A was 64/183 (37.7%) with Helixate NexGen (followed up to 75 exposure days).

In clinical studies with 73 previously treated patients (PTP, defined as having >100 exposure days), followed over 4 years, no de-novo inhibitors were observed.

In extensive post-registration observational studies with Helixate NexGen, involving more than 1000 patients the following was observed: Less than 0.2% PTP developed de-novo inhibitors.

Paediatric population

Frequency, type and severity of adverse reactions in children are expected to be the same as in all population groups except for the inhibitor formation.

Reporting of suspected adverse reactions

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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

No case of overdose with recombinant coagulation factor VIII has been reported.

Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII, ATC code B02BD02.

Mechanism of action

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.

Pharmacodynamic effects

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.

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.

Hypersensitivity

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.

Immune Tolerance Induction (ITI)

Data on Immune Tolerance Induction have been collected in patients with haemophilia A who had developed inhibitors to FVIII. A retrospective review has been done on 40 patients, and 39 patients were included in a prospective investigator-initiated clinical study. Data show that Helixate NexGen has been used to induce immune tolerance. In patients where immune tolerance was achieved the bleedings could be prevented or controlled with Helixate NexGen again, and the patients could continue with prophylactic treatment as maintenance therapy.

Absorption

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.

Distribution and elimination

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

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.

30 months.

After reconstitution, from a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

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". After reconstitution, the chemical and physical in-use stability has been demonstrated for 3 hours in in vitro studies.

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.

Within its overall shelf life of 30 months 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 or the expiration date on the product vial, whichever is earlier. The new expiry date must be noted on the top of the outer carton.

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 alcohol swabs for single use

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

The reconstituted medicinal product is a clear and colourless solution.

Helixate NexGen powder should only be reconstituted with the supplied solvent (2.5 mL (for 250 IU, 500 IU and 1000 IU) or 5 mL (for 2000 IU and 3000 IU) water for injections) using the supplied sterile Mix2Vial filter transfer device. For infusion, the product must be prepared under aseptic conditions. If any component of the package is opened or damaged, do not use this component.

Gently rotate the vial until all powder is dissolved. After reconstitution the solution is clear. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. 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). Helixate NexGen should be reconstituted and administered with the components provided with each package.

The reconstituted product must be filtered prior to administration to remove potential particulate matter in the solution. Filtering is achieved by using the Mix2Vial adapter.

For single use only.

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

Bayer Pharma AG

13342 Berlin

Germany

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

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

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

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

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

Date of first authorisation: 04 August 2000

Date of latest renewal: 06 August 2010

09/2016