REPLENINE®-VF

High Purity Factor IX

1.         Name of Medicinal Product:

NAME OF MEDICINAL PRODUCT

            Replenine®-VF, 50 IU/mL human factor IX, a powder for solution.

2.         Qualitative and Quantitative Composition :

QUALITATIVE AND QUANTITATIVE COMPOSITION

2.1       Qualitative composition

Replenine-VF is a high purity factor IX. This product is prepared from plasma from screened donors. Donors are selected from the USA.

2.2       Quantitative composition

            Replenine-VF is presented as a sterile powder for solution, containing nominally  250 IU, 500 IU or 1000 IU human coagulation factor IX per vial. The product contains approximately 50 IU/mL when reconstituted with either 5 mL (250 IU vial), 10 mL (500 IU vial) or 20 mL (1000 IU vialVial) of Sterilised Water for Injections, Ph.Eur..

One mL of Replenine-VF contains approximately 100 IU of human coagulation factor IX after reconstitution at half volume (see 6.6).

The potency (IU) is determined using the European Pharmacopoeia one stage clotting test. The specific activity of Replenine-VF is approximately 100 IU per mg of protein.

For a full list of excipients, see section 6.1.

3.         Pharmaceutical Form:

PHARMACEUTICAL FORM

Replenine-VF is a powder for solution,; it is a freeze-dried concentrate of factor IX for reconstitution with Sterilised Water for Injections, Ph.Eur...  After reconstitution with the supplied sterile water diluent, the product is administered intravenously.

4.         Clinical Particulars:

CLINICAL PARTICULARS

4.1              4.1       Therapeutic indications

Treatment and prophylaxis in patients with haemophilia B (congenital factor IX deficiency).

4.2              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 dosage and duration of the substitution therapy depend on the severity of the factor IX deficiency, on the location and extent of the bleeding and on the patient’s clinical condition.

On demand treatment

The number of units of factor IX administered is expressed in International Units (IU), which are related to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an international standard for factor IX in plasma).

One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX in one mL of normal human plasma. The calculation of the required dosage of factor IX is based on the empirical finding that 1 International Unit (IU) Replenine-VF per kg body weight raises the plasma factor IX activity by 1.16% of normal activity. The required dosage is determined using the following formula:

Required units = body weight (kg) x desired factor IX rise (%) (IU/dL) x 0.85

The amount to be administered and the frequency of administration should always be orientated to the clinical effectiveness in the individual case. Factor IX products rarely require to be administered more than once daily.

In the case of the following haemorrhagic events, the factor IX activity should not fall below the given plasma activity level (in IU/dL) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:

During the course of treatment, appropriate determination of factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor IX activity) is indispensable. Individual patients may vary in their response to factor IX, achieving different levels of in vivo recovery and demonstrating different half-lives.

Prophylaxis

For long term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 20 to 40 IU of factor IX per kilogram of body weight at intervals of 3 to 4 days.

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

Continuous infusion

An initial pre-operative bolus injection is neededPrior to raisesurgery, a pharmacokinetic analysis should be performed to obtain an estimate of clearance. The initial infusion rate can be calculated as follows:

Clearance x Desired steady state level = Infusion rate (IU/kg/h)

After the factor IX activity to about 100 IU/dL based on formula in the text, above.  A initial 24 hours of continuous infusion is usually started at 6 IU/kg/hour (given undiluted by syringe pump or syringe driver) and adjusted according to , the clearance should be calculated again every day using the factor IX (FIX) activity in plasma monitored at least once daily.  Adjust steady state equation with the rate of infusion according to measured level and the formula:

known rate of infusion (see also section 5.2).

Prophylaxis

For long term prophylaxis against bleeding in patients with severe haemophilia B,

During the usual doses are 20 to 40 IU of factor IX per kilogram of body weight at intervalscourse of    3 to 4 days.

treatment, appropriate determination of factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. In some cases, especially in younger patients, shorter dosage intervals or higher doses the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor IX activity) is indispensable. Individual patients may be necessary. vary in their response to factor IX, achieving different levels of in vivo recovery and demonstrating different half-lives.

In a clinical study in children under six years of age, the median dose of Replenine-VF for prophylaxis was 29.3 IU/kg (95% confidence interval:    25.3 – 33.2 IU/kg) given up to twice weekly; the mean dose to treat a bleed was     26.8 IU/kg (95% confidence interval : 15.7 – 37.9 IU/kg).

Patients should be monitored for the development of factor IX inhibitors. If the expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor IX inhibitor is present.  In patients with high levels of inhibitor, factor IX therapy may not be effective and other therapeutic options should be considered.  Management of such patients should be directed by physicians with experience in the care of patients with haemophilia.

            See also 4.4.

            Method of administration

            Reconstitute the product as described in 6.6. The product should be administered via the intravenous route.  The dose, especially the first dose, should be given slowly (not more than 3 mL per minute).

            For continuous infusion during and after major surgery, the product should be given intravenously and undiluted by a syringe driver or syringe pump (see 4.2).

4.3              4.3      
Contra-indications

            Hypersensitivity to the active substance or to any of the excipients.

4.4                  

4.4              Special warnings and special precautions for usewith other medicaments and other forms of interactions

            As with any intravenous protein product, allergic type hypersensitivity reactions are possible. Replenine-VF contains traces of human proteins other than factor FIX. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur, they should be advised to discontinue use of the product immediately and contact their physician.

In case of shock, standard treatment for shock-treatment should be observed.

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            Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses HAV and parvovirus B19.

It is strongly recommended that every time that Replenine-VF is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

            Appropriate vaccination (hepatitis A and  B) for patients in receipt of plasma-derived  factor IX concentrates is recommended

.

After repeated treatment with human coagulation factor IX products, patients should be monitored for the development of neutralising antibodies (inhibitors) that should be quantified in Bethesda Units (BU) using appropriate biological testing.

There have been reports in the literature showing a correlation between the occurrence of a factor IX inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an increased risk of anaphylaxis with subsequent challenge with factor IX.

Because of the risk of allergic reactions with factor IX concentrates, the initial administrations of factor IX should, according to the treating physician’s judgement, be performed under medical observation where proper medical care for allergic reactions could be provided.

           
Since the use of factor IX complex concentrates has historically been associated with the development of thromboembolic complications, the risk being higher in low purity preparations, the use of factor IX containing products may be potentially hazardous in patients with signs of fibrinolysis and in patients with disseminated intravascular coagulation (DIC). Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to new-born infants, or to patients at risk of thromboembolic phenomena or DIC. In each of these situations, the potential benefit of treatment with Replenine-VF should be weighed against the risk of these complications.

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

4.5              4.5       Interactions with other medicaments medicinal products and other forms of interactions

            No interactions of human coagulation factor IX products with other medicinal products are known.

have been reported.

4.6              4.6       Pregnancy and lactation

            Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence of haemophilia B in women, experience regarding the use of factor IX during pregnancy and breast-feeding is not available.

              Therefore, Replenine-VF should be administered to pregnant and lactating women only if clearly indicated.

4.7              4.7       Effects on ability to drive and use machines

            No effects

            Replenine-VF has no influence on the ability to drive and use machines have been observed.

4.8       Undesirable effects

            The following adverse reactions have been reported from patients in clinical studies and from post-marketing experience (common > 1/100 to <1/10):

            Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently in patients treated with factor IX containing products. In some cases, these reactions have progressed to severe anaphylaxis, and they have occurred in close temporal association with development of factor IX inhibitors (see also 4.4).

Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reaction.

On rare rare occasions, fever has been observed.

Patients with haemophilia B may develop antibodies (inhibitors) to factor IX. If such inhibitors occur, the condition will manifest as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. An inhibitor screening test was positive but the titre was unknown in one patient (a young child, but not a PUP) after treatment for  about 6 months with Replenine-VF. In a clinical study in 15 children aged less than six years, three previously untreated patients were enrolled and remained inhibitor negative after treatment with Replenine-VF for six months.  Of the 67 previously treated patients in clinical studies, one young child developed an inhibitor with a titre of 3.6 Bethesda Units.

There is a potential risk of thromboembolic episodes following the administration of factor IX products, with a higher risk for low purity preparations. The use of low purity factor IX products has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX is rarely associated with such side effects.

For information on viral safety see 4.4.

4.8              4.9       Overdose

            No symptomscase of overdose with human factor IX havehas been reported.

5.         Pharmacological Properties:

PHARMACOLOGICAL PROPERTIES

5.1              5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Antihaemorrhagics: blood coagulation factor IX. ,

ATC code: B02B D04.

Factor IX is a single chain glycoprotein with a molecular mass of about 68,000 Daltons. It is a vitamin K-dependent coagulation factor and it is synthesised in the liver.

               Factor IX is activated by factor XIa in the intrinsic coagulation pathway and by the factor VII/tissue factor complex in the extrinsic pathway. Activated factor IX, in combination with activated factor VIII, activates factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed.

            Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor IX 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 level of factor IX is increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

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

5.2              5.2      
Pharmacokinetic properties

            In a clinical study of 15 adult patients with haemophilia B, the mean pharmacokinetic properties of Replenine-VF were as follows:

            Incremental Recovery:              1.16  IU/dL per IU/kg

            AUC_{0-56 hrs}:                                           15.2  IU./mL/hour

            Terminal Half-life:                                 19.0  hours

            Alpha-Half-life:                         4.8    hours

            Beta-Half-life:                                       20.9  hours

            Mean Residence Time:              24.9  hours

            Clearance:                                            4.52   mL/hour/kg

            Volume of Distribution:             122.1 mL/kg

From clinical studies in 48 adult patients with haemophilia B, most of whom had several assessments of incremental recovery, all based on the maximum FIX:C in the first 1 hour (ISTH, 2001), the overall results were as follows:

Mean               1.25 (95%CI 1.16 – 1.33) IU/dL per IU/kg

Median 1.17 IU/dL per IU/kg

In a clinical trial, when of Replenine-VF was given by continuous infusion to coverfor major surgery, an initial bolus dose was given to raise the factor IX activity to about 100 IU/dL. Continuous infusion was then started at 6 IU/kg/hour (given undiluted by syringe pump or syringe driver). Subsequently, the rate of infusion was adjusted according to the following formula:

New rate = Latest rate          x          Target FIX level (IU/mL)

            (IU/kg/h)       (IU/kg/h)                         Recently recorded FIX level (IU/mL)

 The median clearance was fastest during the first 24 hours peri-operatively (Day 1). Thereafter, median clearance declined as follows: Day 1, 7.3 mL/kg/h; Day 2, 4.2 mL/kg/h; Day 3, 4.4 mL/kg/h; Day 4, 3.4 mL/kg/h; Day 5, 3.2 mL/kg/h; Day 6, 1.3 mL/kg/h. The formula describing the reduction in clearance from post-operative Days 2 to 8 was as follows:

            Factor IX clearance (mL/h/kg) = 5.05 – (0.36 x day)

There was inter-patient variability in clearance so, when covering surgery by continuous infusion, monitoring of plasma factor IX activity is required (see section 4.2).

            Additional data from the study of continuous infusion in major surgery provided the following mean pharmacokinetic values for the period on continuous infusion (by one-compartment multidose analysis):

            Half-life:                                               14.8   hours

            Mean Residence Time:              31.3   hours

            Clearance:                                            3.8     mL/hour/kg

            Volume of Distribution:             107.0  mL/kg

5.3       Preclinical safety data

            Human plasma coagulation factor IX (as contained in Replenine-VF) is a normal constituent of the human plasma and acts like the endogenous factor IX.

            Repeated dose toxicity testing in animals is impracticable due to interference with developing antibodies to heterologous protein. Since clinical experience provides no human plasma coagulation factor IX, experimental studies, particularly in heterologous species, are not considered necessary.

            Single dose toxicity studies in rats and mice have established greater than a 20 fold safety margin. Thrombogenicity testing in rabbits and rats showed no evidence of thrombogenicity at doses of 200-300 IU/kg body weight.

6.         Pharmaceutical Particulars:

PHARMACEUTICAL PARTICULARS

6.1              6.1       List of excipients

Replenine-VF solution contains the following excipients:

glycine

lysine

sodium citrate

sodium phosphate

sodium chloride

polysorbate 80

tri-n-butyl phosphate.

6.2              6.2       Incompatibilities

            This

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

            Only approved injection/infusion sets should be used with the reconstituted product because treatment failure may occur as a consequence of human factor IX adsorption to the internal surface of some unapproved infusion equipment.

6.3              6.3       Shelf-life

When unopened, shelf-life is 36 months at 2°C to 8°C, up to 3 months at normal ambient temperature (25°C) within this period is not detrimental to the product. The expiry date is printed on the label.

            When opened, store at 2°C to 25°C and use within one hour.  Warm to ambient temperature (25°C) before injection.

            Sterilised Water for Injections, Ph.Eur., should be stored between 2°C and 25°C.

6.4       The Transfer Device (Mix2Vial^TM) can be stored in the original carton with Replenine-VF at 2°C to 8°C.

6.4              Special precautions for storage

            Store Replenine-VF in its carton to protect from light at the temperature specified on the packaging. DO NOT FREEZE.  Do not use beyond the expiry date on the label. When the product is for home use a domestic refrigerator is suitable for storage.

6.5              6.5       Nature and contents of container

            Replenine-VF is a freeze-dried plug of high purity factor IX supplied in a single dose vial of either 250 IU, 500 IU or 1000 IU (nominal). The product is contained in glass (type I Ph.Eur.), bottles stoppered with a halobutyl stopper. The bung is over-sealed with a snap-off polypropylene cap and a clear lacquered aluminium skirt.

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

6.6       Instructions for use and handling and disposal

            Reconstitute the product with the Sterilised Water for Injections, Ph.Eur., supplied  (2.5 mL or 5 mL for 250 IU, 5 mL or 10 mL for 500 IU and 10 mL or 20 mL for 1000 IU). Do not use the water if beyond the expiry date or if signs of particulate matter are visible. Do not inject Sterilised Water for Injections, Ph.Eur., on its own.

            Reconstitute Replenine-VF as follows:

            The container of concentrate and the Sterilised Water for Injections, Ph.Eur., should be brought to between 20°C and 30°C, prior to the removal of the 'flip-off' closures. Remove the caps from the concentrate and Sterilised Water for Injections, Ph.Eur., and clean stoppers with a spirit swab. Either of the following methods of reconstitution can then be used:

a)         Using a sterile disposable needle and syringe draw up the required volume of Sterilised Water for Injections, Ph.Eur., and transfer to the vial of the factor IX.  On piercing the seal of the factor IX vial, the water will be drawn into the vial which is under vacuum.

NB:      THE FILTER NEEDLE PROVIDED MUST NOT BE USED TO DRAW UP THE WATER FOR INJECTIONS.

            or

b)         Remove the cover guard from one end of a double ended transfer needle and insert through the stopper into the vial of Sterilised Water for Injections, Ph.Eur..  Remove the other end of the needle guard, invert the water vial over the product vial and insert the free end of the needle through the stopper into the vial of factor IX.  On piercing the seal of the product vial, the water will be drawn into the vial which is under vacuum.  A small amount of water will remain in the water vial. This method cannot be used to prepare the infusion at reduced volume (see above).

            If the water to be used for reconstitution is not drawn into the vial containing factor IX, this indicates loss of vacuum. If the vial does not contain a vacuum or if the reconstituted factor IX forms a gel or a clot, the vial must not be used.

            The container should be agitated to wet the product and the vacuum then released by either:

a)         Removing the syringe from the needle before removing the needle from the product vial;

            or

b)         Disconnecting the two vials by first removing the transfer needle from the water vial and then removing the transfer needle from the product vial.

            Replenine-VF dissolves rapidly and requires only very gentle agitation to ensure complete dissolution. A clear or slightly opalescent solution should be obtained within 5 minutes.  If a gel or clot forms discard the vial.

The solution should be drawn from the vial into a plastic disposable syringe (approved syringes are made by Becton Dickinson) through the filter needle supplied with the product. For administration, a Number 23 "butterfly" needle (Abbott venisystems) is approved for use with this product.

Reconstitute the product with the Sterilised Water for Injections, Ph.Eur., supplied  (2.5 mL or 5 mL for 250 IU, 5 mL or 10 mL for 500 IU and 10 mL or 20 mL for 1000 IU). Do not use the water if beyond the expiry date or if signs of particulate matter are visible. Do not inject Sterilised Water for Injections, Ph.Eur., on its own.

            The container of concentrate and the Sterilised Water for Injections, Ph.Eur., should be brought to between 20°C and 30°C, prior to the removal of the 'flip-off' closures.

You can dissolve your product in two ways using the Transfer Device called Mix2Vial^TM:

(A) Dissolving in Full Volume or 

(B) Dissolving with Half Volume

A) Dissolving in Full Volume

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

Step 1:  Remove the cap from the product vial and clean the top of the stopper with an alcohol swab.  Repeat this step with the sterile water vial.  Peel back the top of the Transfer Device package but leave the device in the package.

Step 2:  Place the blue end of the Transfer Device on the water vial and push straight down until the spike penetrates the rubber stopper and snaps into place.

Remove the plastic outer packaging from the Transfer Device and discard it, taking care not to touch the exposed end of the device.

Step 3:  Turn the water vial upside down with the Transfer Device still attached.

Place the clear end of the Transfer Device on the product vial and push straight down until the spike penetrates the rubber stopper and snaps into place.

Step 4:  The sterile water will be pulled into the product vial by the vacuum contained within it.  Gently swirl the vial to make sure the product is thoroughly mixed.  Do not shake the vial.  A clear or slightly pearl-like solution should be obtained, usually in about 2 to 2½ minutes (5 minutes maximum).

Step 5:    Separate the empty water vial and blue part from the clear part by unscrewing anti-clockwise.  Draw air into the syringe by pulling the plunger to the volume of water added.  Connect the syringe to the white filter and push the air into the vial.

Step 6:  Immediately invert the vial of solution which will be drawn into the syringe.  Disconnect the filled syringe from the device.  Follow normal safety practices to administer your medicine.

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

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

B) Dissolving with Half Volume

This Transfer Device is provided with the product for easy and safe reconstitution.

·        Firstly remove the cap from the Replenine-VF product vial and clean the top of the stopper with an alcohol swab. Repeat this step with the sterile water vial.

To use the Transfer Device for dissolving Replenine-VF in half volumes, it is first necessary to remove and discard half the water volume from the sterile water vial.

·        Pierce the stopper of the sterile water vial with a needle and syringe and draw up half the volume of sterile water.

·        Check that the correct amount is withdrawn.  The needle and syringe containing the water can now be safely disposed of (in the ‘sharps box’).

·        The remaining sterile water in the vial will be used for reconstitution (half the original volume).

·        To complete the dissolving process, follow steps 1 to 6 in Section A above.

·        The product is then ready for administration.

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

The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. Reconstituted products should be inspected visually for particulate matter and discolouration prior to administration.

7.         Marketing Authorisation Holder:

           
7.         MARKETING AUTHORISATION HOLDER

            Bio Products Laboratory

            Dagger Lane

            Elstree

            Hertfordshire

            WD6 3BX

United Kingdom.

Tel: + 44 (0) 20 8258 2200

Fax: + 44 (0) 20 8258 2608

Email: info@bpl.co.uk

8.         Marketing Authorisation Number:

8.         MARKETING AUTHORISATION NUMBER

            PL 08801/0028

9.         Date of First Authorisation/Renewal of Authorisation:

9 August 1999

10.       Date of (Partial) Revision of the Text:

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

9^th August 1999

10.       DATE OF REVISION OF TEXT