NONAFACT 100UI / ml lyophilizate + solvent for solution medication leaflet

Nonafact 100 IU/ml powder and solvent for solution for injection.

Nonafact contains 100 IU/ml (500 IU/5ml or 1000 IU/10ml) human coagulation factor IX whenreconstituted with 5 ml or 10 ml, respectively, of water for injections.

Each vial contains 500 IU or 1000 IU of human coagulation factor IX.

The potency (IU) is determined using a method equivalent to the test method described in the

European Pharmacopoeia. The specific activity of Nonafact is at least 200 IU/mg protein.

For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection. White powder.

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

Treatment should be initiated under the supervision of a physician experienced in the treatment ofhaemophilia.

The dose and the duration of substitution therapy depend on the severity of the factor IX deficiency.

Other determining factors are the site and extent of the haemorrhage and the patient’s clinicalcondition.

The number of units of factor IX administered is expressed in International Units (IU), which arerelated to the current International Standard for factor IX concentrate as approved by the WHO. 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 related to the quantity of factor IX in the

International Standard for factor II, VII, IX and X in human plasma (approved by the WHO) whichapproximates to the quantity of factor IX in one ml of normal human plasma. The calculation of therequired dosage of factor IX is based on the empirical finding that 1 International Unit (IU) factor IXper kg body weight raises the plasma factor IX activity by 1.1 % of normal activity. The requireddosage is determined using the following formula:

Required units = body weight (kg) x desired factor IX rise (%) (IU/dl) x 0.9

The amount to be administered and the frequency of treatment should always be determined on thebasis of clinical effectiveness in the individual patient. Factor IX products rarely require to beadministered more than once daily.

In the case of the following haemorrhagic events, the factor IX activity should not fall below the givenplasma activity level (in % of normal or IU/dl) in the corresponding period. The following table can beused to guide dosing in bleeding episodes and surgery:

Degree of haemorrhage/Type of Factor IX level Frequency of doses (hours)/Durationsurgical procedure required (%) of therapy (days)(IU/dl)

Early haemarthrosis, muscle 20-40 Repeat every 24 hours. At least 1bleeding or oral bleeding day, until the bleeding episode asindicated by pain is resolved orhealing is achieved.

More extensive haemarthrosis, 30-60 Repeat infusion every 24 hours formuscle bleeding or haematoma 3-4 days or more until pain andacute disability are resolved.

Life threatening haemorrhages 60-100 Repeat infusion every 8 to 24 hoursuntil threat is resolved.

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

Major 80-100 Repeat infusion every 8-24 hoursuntil adequate wound healing, then(pre- and therapy for at least another 7 days topostoperative) maintain a factor IX activity of 30 %to 60 % (IU/dl).

During the course of treatment, appropriate determination of factor IX levels is advised to guide thedose to be administered and the frequency of repeated injections. In the case of major surgicalinterventions in particular, precise monitoring of 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.

For long-term prophylaxis of haemorrhages in patients with severe haemophilia B, doses of 20 to 40

IU of factor IX per kilogram of body weight could be given at intervals of 3 to 4 days.

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

The safety and efficacy of Nonafact in children less than 6 years of age has not been established.

There are insufficient data to recommend the use of Nonafact in children less than 6 years of age.

Patients should be monitored for the development of factor IX inhibitors. If the expected factor IXactivity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, anassay should be performed to determine if a factor IX inhibitor is present. In patients with high levelsof 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 patientswith haemophilia, see also 4.4.

The product should be administered via the intravenous route. It is recommended that the rate ofadministration should not exceed 2 ml/min. For instructions on reconstitution of the medicinal productbefore administration, see section 6.6.

- Hypersensitivity to the active substance or to any of the excipients;

- Hypersensitivity to mouse proteins.

As with any intravenous protein product, allergic type hypersensitivity reactions are possible. Theproduct contains traces of mouse proteins. Patients should be informed of the early signs ofhypersensitivity reactions including urticaria, tightness of the chest, wheezing, hypotension, andanaphylaxis. If these symptoms occur, patients should be advised to discontinue use of the productimmediately and contact their physician.

In case of shock, the current medical standards for shock-treatment should be observed.

Since the use of factor IX complex concentrates has historically been associated with the developmentof 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 inpatients with disseminated intravascular coagulation (DIC). Because of the potential risk of thromboticcomplications, clinical surveillance for early signs of thrombotic and consumptive coagulopathyshould be initiated with appropriate biological testing when administering this product to patients withliver disease, to patients post-operatively, to new-born infants, or to patients at risk of thromboticphenomena or DIC. In each of these situations, the benefit of treatment with Nonafact should beweighed against the risk of these complications.

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

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

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeatedreceipt of plasma-derived factor IX concentrates.

It is strongly recommended that every time that Nonafact is administered to a patient, the name andbatch number of the product are recorded in order to maintain a link between the patient and the batchof the product.

After repeated treatment with Nonafact, patients should be monitored for the development ofneutralising antibodies (inhibitors) that should be quantified in Bethesda Units (BU) using appropriatebiological testing.

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

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

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.

No interactions of Nonafact with other medicinal products are known.

Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence ofhaemophilia B in women, experience regarding the use of factor IX during pregnancy and breast-feeding is not available. Therefore, factor IX should be used during pregnancy and lactation only ifclearly indicated.

Nonafact has no influence on the ability to drive and 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 observedinfrequently in patients treated with factor IX containing products. In some case, these reactions haveprogressed to severe anaphylaxis, and they have occurred in close temporal association withdevelopment of factor IX inhibitors (see also 4.4).

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

On rare occasions, fever has been observed.

Haemophilia B patients may develop antibodies (inhibitors) to factor IX. If such inhibitors occur, thecondition will manifest itself as an insufficient clinical response. In such cases, it is recommended thata specialised haemophilia centre be contacted. During clinical trials with Nonafact conducted inpreviously treated patients development of inhibitors was not reported. There is no experience of thetreatment of previously untreated patients with Nonafact.

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

Nonafact contains trace amounts (< 0.1 ng mouse IgG/IU of factor IX) of the murine monoclonalantibody used in its purification. In theory, therefore, the use of Nonafact could generate antibodies tomouse protein. The clinical relevance of antibodies to mouse protein, if these do indeed arise, is notknown.

For safety with respect to transmissible agents, see 4.4.

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

Pharmacotherapeutic Group: antihaemorrhagics, blood coagulation factor IX. ATC code: B02BD04.

Factor IX is a single chain glycoprotein with a molecular weight of about 68,000 Dalton. It is avitamin K-dependent coagulation factor and 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 extrinsicpathway. Activated factor IX, in combination with activated factor VIII, activates factor X. Activatedfactor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clotis formed. Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreasedlevels of factor IX 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 IX are increased, thereby enabling a temporary correction of the factor IX deficiency andcorrection of the bleeding tendencies.

There are insufficient data to recommend the use of Nonafact in children less than 6 years of age.

The in vivo increase in factor IX levels obtained with Nonafact is 1.1 IU/dl per IU administered per kgbody weight, which corresponds to an in vivo recovery of 49 %. Nonafact has a half-life ofapproximately 19 (17 - 21) hours.

Plasma coagulation factor IX is a normal constituent of human plasma. Factor IX in this producttherefore behaves like endogenous factor IX. Conventional animal toxicity studies and mutagenicitystudies with plasma coagulation factor IX were not carried out. In pharmacodynamic studies in rabbitsand guinea pigs, the thrombogenicity of Nonafact was shown to be minimal.

Sodium chloride

Sucrose

Histidine.

Water for injections.

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

2 years

Chemical and physical in-use stability has been demonstrated for 3 hours at a temperature of 21°C.

From a microbiological point of view, the product should be used immediately.If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 to 8 0C, unless reconstitution/dilution (etc) has takenplace in controlled and validated aseptic conditions.

Store in a refrigerator (at 2°C - 8°C ). Do not freeze. Keep the vials in the outer carton, in order toprotect from light. For storage conditions of the reconstituted medicinal product, see section 6.3.

500 IU: one vial (glass type I) of powder + one vial (glass type I) of 5 ml solvent with stoppers(bromobutyl).

1000 IU: one vial (glass type I) of powder + one vial (glass type I) of 10 ml solvent with stoppers(bromobutyl).

Reconstitution1. Bring the two vials to a temperature between 15°C and 25°C.2. Remove the plastic cap from the vials.3. Disinfect the surface of the stoppers of both vials with a gauze soaked in 70 % alcohol.4. Remove the protective sheath from one end of a transfer needle and pierce the stopper of thevial containing water for injections. Remove the protective sheath from the other end of thetransfer needle. Invert the solvent vial and pierce the stopper of the vial containing the powder.

5. Tilt the product vial when transferring the solvent to allow the solvent to flow down the side ofthe vial.

6. Remove the empty vial and the transfer needle.7. Swirl the vial gently to completely dissolve the powder within 5 minutes. The resulting solutionis clear, colourless to light yellow and has a neutral pH.

Reconstituted products should be inspected visually for particulate matter and discoloration prior toadministration. The solution should be clear or slightly opalescent. Do not use solutions that arecloudy or have deposits.

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

Sanquin

Plesmanlaan 125

NL-1066 CX Amsterdam

The Netherlands

EU/1/01/186/001 (500 IU)

EU/1/01/186/002 (1000 IU)

Date of first authorisation: 3 July 2001

Renewal of authorisation: 3 July 2006

Detailed information on this product is available on the website of the European Medicines Agency(EMA) http://www.ema.europa.eu.