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1. Replenine-Vf 50 Iu/Ml Human Factor Ix A Powder For Solution
2. Replenine-Vf 50 Iu/Ml Human Factor Ix A Powder For Solution

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SUMMARY OF PRODUCT CHARACTERISTICS 1    NAME OF THE MEDICINAL PRODUCT

REPLENINE ®-VF, 50 IU/ml human factor IX, a powder for solution.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

2.1    Qualitative composition

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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, 500 or 1000 IU human coagulation factor IX per vial. The product contains approximately 50 IU/mL when reconstituted with either 5mL (250 IU vial), 10mL (500 IU vial) or 20mL (1000 IU Vial) of Sterilised Water for Injections, Ph.Eur.

The potency (IU) is determined using the European Pharmacopoeia one stage

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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

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

4.1 Therapeutic indications

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

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) factor IX 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:

Degree of haemorrhage/ Type of surgical procedure	Factor IX level required (%) (IU/dl)	Frequency of doses (hours)/ Duration of therapy (days)
		Repeat every 24 hours. At least
Haemorrhage	20-40	1 day, until the bleeding
Early haemarthrosis, muscle		episode as indicated by pain is
bleeding or oral bleeding		resolved or healing is achieved.
	30-60	Repeat infusion every 24 hours
More extensive		for 3-4 days or more until pain
haemarthrosis, muscle bleeding or haematoma.		and disability are resolved.
	60-100	Repeat infusion every 8 to 24
Life threatening haemorrhages.		hours until threat is resolved.
Surgery
Minor surgery	30-60	Every 24 hours, at least 1 day, until healing is achieved.
Including tooth extraction	80-100	Repeat infusion every 8-24 hours until adequate wound
	(pre- and	healing, then therapy for at
Major surgery	postoperative)	least another 7 days to maintain a FIX activity of 30% to 60% (IU/dl).

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.

Continuous infusion

An initial pre-operative bolus injection is needed to raise the factor IX activity to about 100 IU/dL based on the formula in the text, above. A continuous infusion is usually started at 6 IU/kg/hour (given undiluted by syringe pump or syringe driver) and adjusted according to the factor IX activity in plasma monitored at least once daily. Adjust the rate of infusion according to the formula:

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

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

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. 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 undiluted product should be given intravenously by a syringe driver or syringe pump (see 4.2).

4.3 Contraindications

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

4.4 Special warnings and precautions for use

As with any intravenous protein product, allergic type hypersensitivity

reactions are possible. REPLENINE -VF contains traces of human proteins other than 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.

-    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.

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-    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

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time that REPLENINE -VF is administered to them, the name and batch number of the product is registered.

4.5 Interaction with other medicinal products and other forms of interaction

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

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 used during pregnancy and lactation only if clearly indicated.

4.7 Effects on ability to drive and use machines

No effects on 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 experience.:

MedDRA Standard System Organ Class	Adverse reactions	Frequency
Nervous system disorders	Headache	common > 1/100 to <1/10
General disorders and injection site changes	injection site reaction	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 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. 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. The median number of exposure days in these patients was 43 (range 26-54). Of the 67 PTP patients in clinical studies, one young child developed an inhibitor 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.

4.9 Overdose

No symptoms of overdose with human factor IX have been reported.

5 PHARMACOLOGICAL PROPERTIES

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. 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

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REPLENINE -VF experienced less bleeds than those only using it on demand. For doses in children see 4.2.

5.2 Pharmacokinetic properties

In a clinical study of 15 adult patients with haemophilia B, the mean

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pharmacokinetic properties of REPLENINE -VF were as follows:

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 REPLENINE -VF was given by continuous infusion to cover major surgery, 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):

Mean Residence Time: Clearance:

Volume of Distribution:

5.3 Preclinical safety data

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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 evidence for tumourigenic and mutagenic effects of 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

6.1 List of excipients

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REPLENINE -VF solution contains the following excipients :

glycine

lysine

sodium citrate sodium phosphate sodium chloride polysorbate 80 tri-n-butyl phosphate.

6.2 Incompatibilities

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 Shelf life

When unopened, shelf-life is 36 months at 2°C to 8°C, and 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 (25°C) before injection.

6.4 Special precautions for storage

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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.

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

6.5 Nature and contents of container

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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 oversealed with a snap-off polypropylene cap and a clear lacquered aluminium skirt.

6.6 Special precautions for 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.

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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.

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

Bio Products Laboratory Limited Dagger Lane

Elstree Hertfordshire WD6 3BX United Kingdom.

8    MARKETING AUTHORISATION NUMBER(S)

PL 08801/0054

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

26/05/2010

10    DATE OF REVISION OF THE TEXT

07/11/2012