1. Name Of The Medicinal Product
KOGENATE Bayer 500 IU powder and solvent for solution for injection.
2. Qualitative And Quantitative Composition
2.1 General description
Each vial contains nominally 500 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
One ml of KOGENATE Bayer 500 IU contains approximately 200 IU (500 IU / 2.5 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 KOGENATE Bayer is approximately 4000 IU/mg protein.
Solvent: water for injections.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder and solvent for solution for injection.
Powder: dry white to slightly yellow powder or cake.
Solvent: water for injection, a clear, colourless solution.
The reconstituted medicinal product is a clear and colourless solution.
4. Clinical Particulars
4.1 Therapeutic Indications
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.
4.2 Posology And Method Of Administration
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
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II. Expected factor VIII rise (% of normal) =
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2 × administered IU
body weight (kg)
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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:
Degree of haemorrhage/ Type of surgical procedure
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Factor VIII level required (%) (IU/dl)
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Frequency of doses (hours)/ Duration of therapy (days)
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Haemorrhage
Early haemarthrosis, muscle bleed or oral bleed
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20 - 40
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Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.
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More extensive haemarthrosis, muscle bleed or haematoma
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30 - 60
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Repeat infusion every 12 - 24 hours for 3 - 4 days or more until pain and disability are resolved.
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Life threatening bleeds such as intracranial bleed, throat bleed, severe abdominal bleed
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60 - 100
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Repeat infusion every 8 to 24 hours until threat is resolved
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Surgery
Minor
including tooth extraction
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30 - 60
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Every 24 hours, at least 1 day, until healing is achieved.
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Major
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80 - 100
(pre- and postoperative)
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a) By bolus infusions
Repeat infusion every 8 - 24 hours until adequate wound healing occurs, then continue with therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60%
b) By continuous infusion
Raise factor VIII activity pre-surgery with an initial bolus infusion and immediately follow with continuous infusion (in IU/Kg/h) adjusting according to patient's daily clearance and desired factor VIII levels for at least 7 days.
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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 KOGENATE Bayer 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. KOGENATE Bayer 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 KOGENATE Bayer 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 KOGENATE Bayer. 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.
KOGENATE Bayer 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
KOGENATE Bayer 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
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Desired plasma FVIII level
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Infusion rate
IU/h/kg
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Infusion rate for 75 kg patient
ml/h
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Clearance: 3 ml/h/kg
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Concentrations of rFVIII solution
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100 IU/ml
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200 IU/ml
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400 IU/ml
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100 % (1 IU/ml)
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3.0
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2.25
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1.125
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0.56
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60 % (0.6 IU/ml)
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1.8
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1.35
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0.68
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0.34
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40 % (0.4 IU/ml)
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1.2
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0.9
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0.45
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0.225
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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.
4.3 Contraindications
- Known hypersensitivity to the active substance or to any of the excipients.
- Known allergic reactions to mouse or hamster protein.
4.4 Special Warnings And Precautions For Use
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 patient 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 KOGENATE Bayer 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”.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No interactions of KOGENATE Bayer with other medicinal products are known.
4.6 Pregnancy And Lactation
Animal reproduction studies have not been conducted with KOGENATE Bayer.
Based on the rare occurrence of haemophilia A in women, experience regarding the use of KOGENATE Bayer during pregnancy and breast-feeding is not available. Therefore, KOGENATE Bayer should be used during pregnancy and breast-feeding only if clearly indicated.
There are no fertility data available.
4.7 Effects On Ability To Drive And Use Machines
KOGENATE Bayer has no influence on the ability to drive or to use machines.
4.8 Undesirable Effects
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 KOGENATE Bayer are summarized in the table below. Within each frequency group, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as common (
MedDRA Standard
System Organ Class
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Common
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Uncommon
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Rare
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Blood and the Lymphatic System Disorders
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Inhibitor Formation to FVIII
(Reported in PUP and minimally treated patients in clinical trials)*
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Inhibitor Formation to FVIII
(Reported in PTP in clinical trials and Post Marketing Studies)*
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General Disorders and Administration Site Conditions
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Infusion site reaction
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Infusion related febrile reaction (pyrexia)
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Immune System Disorders
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Skin associated hypersensitivity reactions, (pruritus, urticaria and rash)
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Systemic Hypersensitivity reactions (including one anaphylactic reaction, nausea, blood pressure abnormal and, dizziness)
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* 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, KOGENATE Bayer 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 KOGENATE Bayer 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 KOGENATE Bayer, 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).
4.9 Overdose
No case of overdose with recombinant coagulation factor VIII has been reported.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII, ATC code B02BD02.
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 KOGENATE Bayer is similar to that achieved with plasma-derived factor VIII.
5.2 Pharmacokinetic Properties
The analysis of all recorded in vivo recoveries in previously treated patients demonstrated a mean rise of 2 % per IU/kg body weight for KOGENATE Bayer. This result is similar to the reported values for factor VIII derived from human plasma.
After administration of KOGENATE Bayer, 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 KOGENATE Bayer 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).
5.3 Preclinical Safety Data
Even doses several fold higher than the recommended clinical dose (related to body weight) failed to demonstrate any acute or subacute toxic effects for KOGENATE Bayer 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 KOGENATE Bayer, since no mutagenic potential could be detected in vitro or in vivo for the predecessor product of KOGENATE Bayer.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Powder
Glycine
Sodium chloride
Calcium chloride
Histidine
Polysorbate 80
Sucrose
Solvent
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6..
Only the provided components (powder vial, pre-filled syringe containing solvent, vial adapter and venipuncture set) should be used for reconstitution and injection because treatment failure can occur as a consequence of human recombinant coagulation factor VIII adsorption to the internal surfaces of some infusion equipment.
6.3 Shelf Life
30 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.
6.4 Special Precautions For Storage
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial and the pre-filled syringe 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 outer carton.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature And Contents Of Container
Each package of KOGENATE Bayer contains:
• one vial with powder (10 ml clear glass type 1 vial with latex-free grey halogenobutyl rubber blend stopper and aluminium seal)
• one pre-filled syringe with 2.5 ml solvent (clear glass cylinder type 1 with latex-free grey bromobutyl rubber blend stopper)
• syringe plunger rod
• vial adapter
• one venipuncture set
• two sterile alcohol swabs for single use
• two dry swabs
• two plasters
6.6 Special Precautions For Disposal And Other Handling
Detailed instructions for preparation and administration are contained in the package leaflet provided with KOGENATE Bayer.
KOGENATE Bayer powder should only be reconstituted with the supplied solvent (2.5 ml water for injections) in the prefilled syringe and the vial adapter. 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 KOGENATE Bayer if you notice visible particulate matter or turbidity.
After reconstitution, the solution is drawn back into the syringe.
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.
7. Marketing Authorisation Holder
Bayer Pharma AG
13342 Berlin
Germany
8. Marketing Authorisation Number(S)
EU/1/00/143/008
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 04 August 2000
Date of latest renewal: 06 August 2010
10. Date Of Revision Of The Text
1 July 2011
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
