KOGENATE BAYER 250UI powder + solvent for injection medication leaflet

KOGENATE Bayer 250 IU powder and solvent for solution for injection

KOGENATE Bayer 500 IU powder and solvent for solution for injection

KOGENATE Bayer 1000 IU powder and solvent for solution for injection

KOGENATE Bayer 2000 IU powder and solvent for solution for injection

KOGENATE Bayer 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 hamsterkidney cells containing the human factor VIII gene.

* One mL KOGENATE Bayer 250 IU contains approximately 100 IU (250 IU/2.5 mL) ofrecombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with waterfor injections.

* One mL KOGENATE Bayer 500 IU contains approximately 200 IU (500 IU/2.5 mL) ofrecombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with waterfor injections.

* One mL KOGENATE Bayer 1000 IU contains approximately 400 IU (1000 IU/2.5 mL) ofrecombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with waterfor injections.

* One mL KOGENATE Bayer 2000 IU contains approximately 400 IU (2000 IU/5 mL) ofrecombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with waterfor injections.

* One mL KOGENATE Bayer 3000 IU contains approximately 600 IU (3000 IU/5 mL) ofrecombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with waterfor injections.

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

The specific activity of KOGENATE Bayer is approximately 4000 IU/mg protein.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection (Bio-Set System).

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 VIIIdeficiency). This preparation does not contain von Willebrand factor and is therefore not indicated invon 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.

The number of units of factor VIII administered is expressed in International Units (IU), which arerelated to the current WHO standard for factor VIII products. Factor VIII activity in plasma isexpressed either as a percentage (relative to normal human plasma) or in International Units (relativeto the International Standard for factor VIII in plasma).

One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII inone mL of normal human plasma.

The calculation of the required dose of factor VIII is based on the empirical finding that1 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

II. Expected factor VIII rise (% of normal) = 2 × administered IUbody weight (kg)

The dose, frequency and duration of the substitution therapy must be individualised according to thepatient's needs (weight, severity of disorder of the haemostatic function, the site and extent of thebleeding, 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 thehaemorrhagic events listed, the factor VIII activity should not fall below the given level (in % ofnormal) in the corresponding period:

Table 1: Guide for dosing in bleeding episodes and surgery

Degree of haemorrhage/ Factor VIII level Frequency of doses (hours)/

Type of surgical procedure required (%) (IU/dl) Duration of therapy (days)

Early haemarthrosis, muscle 20 - 40 Repeat every 12 to 24 hours. Atbleed or oral bleed least 1 day, until the bleedingepisode as indicated by pain isresolved or healing is achieved.

More extensive haemarthrosis, 30 - 60 Repeat infusion every 12 - 24 hoursmuscle bleed or haematoma for 3 - 4 days or more until pain anddisability are resolved.

Life threatening haemorrhages 60 - 100 Repeat infusion every 8 to 24 hours(such as intracranial bleed, until threat is resolvedthroat bleed, severe abdominalbleed)

Minor 30 - 60 Every 24 hours, at least 1 day, untilincluding tooth extraction healing is achieved.

Major 80 - 100 a) By bolus infusions(pre- and Repeat infusion every 8 - 24 hourspostoperative) until adequate wound healingoccurs, then continue with therapyfor at least another 7 days tomaintain a factor VIII activity of30% to 60% (IU/dl).b) By continuous infusion

Raise factor VIII activity pre-surgery with an initial bolusinfusion and immediately followwith continuous infusion (in

IU/kg/h) adjusting according topatient’s daily clearance and desiredfactor VIII levels for at least 7 days.

The amount to be administered and the frequency of administration should always be adaptedaccording to the clinical effectiveness in the individual case. Under certain circumstances largeramounts 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 toguide the dose to be administered and the frequency at which to repeat the infusions. In the case ofmajor surgical interventions in particular, precise monitoring of the substitution therapy by means ofcoagulation analysis (plasma factor VIII activity) is indispensable. Individual patients may vary intheir 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-surgerydecay curve, or by starting from an average population value (3.0-3.5 mL/h/kg) and then adjustaccordingly.

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 pumpswith a PVC reservoir. KOGENATE Bayer contains low level of polysorbate-80 as an excipient, whichis 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.

For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are20 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.

The safety and efficacy of KOGENATE Bayer in children of all ages have been established. Data havebeen obtained from clinical studies in 61 children under 6 years of age and non-interventional studiesin children of all ages.

Patients with inhibitors

Patients should be monitored for the development of factor VIII inhibitors. If the expected plasmafactor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, anassay should be performed to determine if a factor VIII inhibitor is present. If the inhibitor is present atlevels less than 10 Bethesda Units (BU) per mL, administration of additional recombinant coagulationfactor 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 mustbe adjusted according to clinical response and monitoring of plasma factor VIII activity. In patientswith inhibitor titres above 10 BU or with high anamnestic response, the use of (activated) prothrombincomplex concentrate (PCC) or recombinant activated factor VII (rFVIIa) preparations has to beconsidered. These therapies should be directed by physicians with experience in the care of patientswith haemophilia.

KOGENATE Bayer should be injected intravenously over 2 to 5 minutes. The rate of administrationshould 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 calculatedbased 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 bolusinjection

Desired plasma Infusion rate Infusion rate for 75 kg patient

FVIII level IU/h/kg mL/h

Clearance: Concentrations of rFVIII solution3 mL/h/kg 100 IU/mL 200 IU/mL 400

IU/mL100 % (1 IU/mL) 3.0 2.25 1.125 0.5660 % (0.6 IU/mL) 1.8 1.35 0.68 0.3440 % (0.4 IU/mL) 1.2 0.9 0.45 0.225

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

After the initial 24 hours of continuous infusion, the clearance should be recalculated every day usingthe steady state equation with the measured FVIII level and the rate of infusion using the followingequation: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 andthe package leaflet.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Known allergic reactions to mouse or hamster protein.

Allergic type hypersensitivity reactions are possible with KOGENATE Bayer. The product containstraces of mouse and hamster proteins and human proteins other than factor VIII (see section 5.1).

If symptoms of hypersensitivity occur, patients should be advised to discontinue the use of themedicinal 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.

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in themanagement of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulinsdirected 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 theseverity of the disease as well as the exposure to factor VIII, this risk being highest within the first20 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 factor VIIIproduct to another in previously treated patients with more than 100 exposure days who have aprevious history of inhibitor development. Therefore, it is recommended to monitor all patientscarefully for inhibitor occurrence following any product switch.

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titreinhibitors which are transiently present or remain consistently low titre posing less of a risk ofinsufficient clinical response than high titre inhibitors.

In general, all patients treated with coagulation factor VIII products should be carefully monitored forthe 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 withan appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients withhigh levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options shouldbe considered. Management of such patients should be directed by physicians with experience in thecare of haemophilia and factor VIII inhibitors.

Continuous infusion

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

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

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

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

Documentation

It is strongly recommended that every time that KOGENATE Bayer is administered to a patient, thename and batch number of the product are recorded in order to maintain a link between the patient andthe batch of the medicinal product.

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

No interactions of KOGENATE Bayer with other medicinal products have been reported.

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.

KOGENATE Bayer has no influence on the ability to drive or to use machines.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at theinfusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea,restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observedwith 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 tosevere anaphylaxis (including shock) is considered to be rare.

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treatedwith factor VIII, including with KOGENATE Bayer. If such inhibitors occur, the condition willmanifest itself as an insufficient clinical response. In such cases, it is recommended that a specialisedhaemophilia centre be contacted.

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

MedDRA Frequency

Standard Very common Common Uncommon Rare Very

System Organ Rare/not

Class known

Blood and the FVIII FVIII

Lymphatic Inhibition Inhibition

System (PUPs)* (PTPs)*

Disorders

General Infusion site Infusion related

Disorders and reaction febrile reaction

Administratio (pyrexia)n Site

Conditions

Immune Skin associated Systemic

System hypersensitivity Hypersensitivit

Disorders reactions, y reactions(pruritus, (includingurticaria and anaphylacticrash) reaction,nausea, bloodpressureabnormal and,dizziness)

Nervous Dysgeusia

System

Disorders

* Frequency is based on studies with all FVIII products which included patients with severehaemophilia A. PTPs = previously-treated patients, PUPs = previously untreated patients

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

The factor VIII/von Willebrand factor (vWF) complex consists of two molecules (factor VIII andvWF) with different physiological functions. When infused into a haemophilic patient, factor VIIIbinds 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 convertsprothrombin 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 offactor VIII:C and results in profuse bleeding into joints, muscles or internal organs, eitherspontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levelsof factor VIII are increased, thereby enabling a temporary correction of the factor deficiency andcorrection of the bleeding tendencies.

Determination of activated partial thromboplastin time (aPTT) is a conventional in vitro assay methodfor biological activity of factor VIII. The aPTT is prolonged in all haemophiliacs. The degree andduration of aPTT normalisation observed after administration of KOGENATE Bayer is similar to thatachieved with plasma-derived factor VIII.

Continuous Infusion

It has been shown in a clinical study performed with adult haemophilia A patients who undergo amajor surgery that KOGENATE Bayer can be used for continuous infusion in surgeries (pre-, duringand postoperative). In this study heparin was used to prevent thrombophlebitis at the infusion site aswith any other long term intravenous infusions.

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

Immune Tolerance Induction (ITI)

Data on Immune Tolerance Induction have been collected in patients with haemophilia A who haddeveloped inhibitors to FVIII. A retrospective review has been done on 40 patients, and 39 patientswere included in a prospective investigator-initiated clinical study. Data show that KOGENATE

Bayer has been used to induce immune tolerance. In patients where immune tolerance was achievedthe bleedings could be prevented or controlled with KOGENATE Bayer again, and the patients couldcontinue with prophylactic treatment as maintenance therapy.

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

Distribution and elimination

After administration of KOGENATE Bayer, peak factor VIII activity decreased by a two-phaseexponential 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. Additionalpharmacokinetic 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 for14 adult patients undergoing major surgeries with continuous infusion are 188 mL/h corresponding to3.0 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 todemonstrate 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, andcarcinogenicity were not performed with octocog alfa due to the immune response to heterologousproteins in all non-human mammalian species.

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

Glycine

Sodium chloride

Calcium chloride

Histidine

Polysorbate 80

Sucrose

Water for injections

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

Only the provided components (powder vial with Bio-Set system, pre-filled syringe containing solventand venipuncture set) should be used for reconstitution and injection because treatment failure canoccur as a consequence of human recombinant coagulation factor VIII adsorption to the internalsurfaces of some infusion equipment.

30 months.

After reconstitution, from a microbiological point of view, the product should be used immediately. Ifnot used immediately, in-use storage times and conditions prior to use are the responsibility of theuser.

However, during in vitro studies, the chemical and physical in-use stability has been demonstrated for24 hours at 30°C in PVC bags for continuous infusion'. After reconstitution, the chemical andphysical 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 vial and the pre-filled syringe in the outercarton 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 atambient room temperature (up to 25°C) for a limited period of 12 months. In this case, the productexpires at the end of this 12-month period or the expiration date on the product vial, whichever isearlier. The new expiry date must be noted on the outer carton.

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

implantation

Each package of KOGENATE Bayer contains:

* one vial plus Bio-Set system, containing powder (10 mL clear glass type 1 vial with latex-free greyhalogenobutyl rubber blend stopper plus transfer system with protective cap [Bio-Set])

* one pre-filled syringe with 2.5 mL (for 250 IU, 500 IU and 1000 IU) or 5 mL (for 2000 IU and3000 IU) solvent (clear glass cylinder type 1 with latex-free grey bromobutyl rubber blend stopper)

* syringe plunger rod

* one venipuncture set

* two alcohol swabs for single use

* two dry swabs

* two plasters

Detailed instructions for preparation and administration are contained in the package leaflet providedwith KOGENATE Bayer.

The reconstituted medicinal product is a clear and colourless solution.

KOGENATE Bayer powder should only be reconstituted with the supplied solvent (2.5 mL (for250 IU, 500 IU and 1000 IU) or 5 mL (for 2000 IU and 3000 IU) water for injections) in the prefilledsyringe and the integrated transfer system (Bio-Set). For infusion, the product must be prepared underaseptic 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. Parenteraldrug products should be inspected visually for particulate matter and discoloration prior toadministration. Do not use KOGENATE Bayer if you notice visible particulate matter or turbidity.

After reconstitution, the solution is drawn back into the syringe. KOGENATE Bayer should bereconstituted and administered with the components provided with each package.

The reconstituted product must be filtered prior to administration to remove potential particulatematter in the solution. Filtering can be achieved by following the reconstitution and/or administrationsteps as described in the package leaflet provided with KOGENATE Bayer. It is important to use thevenipuncture set provided with the product for administration as it incorporates an in-line filter.

In situations where the venipuncture set provided cannot be used (e.g. when infusing into a peripheralor central line), a separate filter compatible with KOGENATE Bayer should be used. Thesecompatible filters are luer adaptor-type of Polyacrylic housing with integrated filter element of a

Polyamide screen of 5 - 20 micrometer mesh size.

The venipuncture set provided with the product must not be used for drawing blood because itcontains an in-line filter. When blood must be withdrawn prior to an infusion, use an administrationset without a filter, then infuse KOGENATE Bayer through an injection filter.

If you have any questions about KOGENATE Bayer and compatible separate filters contact Bayer

AG.

For single use only.

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

Bayer AG51368 Leverkusen

Germany

EU/1/00/143/004 - KOGENATE Bayer 250 IU

EU/1/00/143/005 - KOGENATE Bayer 500 IU

EU/1/00/143/006 - KOGENATE Bayer 1000 IU

EU/1/00/143/010 - KOGENATE Bayer 2000 IU

EU/1/00/143/012 - KOGENATE Bayer 3000 IU

Date of first authorisation: 04 August 2000

Date of latest renewal: 06 August 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.