Nonafact - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Nonafact contains 100 IU/ml (500 IU/5ml or 1000 IU/10ml) human coagulation factor IX when reconstituted 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.

3. PHARMACEUTICAL FORM

Powder and solvent for solution for injection. White powder.

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

Posology

Treatment should be initiated un haemophilia.

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 clinical condition.

The number of units of factor IX administered is expressed in International Units (IU), which are related 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) which approximates to the 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 1.1 % 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 0.9

The amount to be administered and the frequency of treatment should always be determined on the basis of clinical effectiveness in the individual patient. 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 % of normal or 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)
Haemorrhage
Early haemarthrosis, muscle bleeding or oral bleeding	20–40	Repeat every 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.
More extensive haemarthrosis, muscle bleeding or haematoma	30–60	Repeat infusion every 24 hours for 3–4 days or more until pain and acute disability are resolved.
Life threatening haemorrhages	60–100	Repeat infusion every 8 to 24 hours until threat is resolved.
Surgery Minor including tooth extraction	30–60	.,…, Every 24 hours, at least 1 day, until healing is achieved.
Major	80–100 (pre- and postoperative)	Repeat infusion every 8–24 hours until adequate wound healing, then therapy for at least another 7 days to 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 the dose to be administered and the frequency of repeated injections. In the case of major surgical interventions 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

evels 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 be necessary.

Paediatric population

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 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

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

4.3 Contraindications

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

Hypersensitivity to mouse proteins.

4.4 Special warnings and precautions for use

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

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

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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 thrombotic phenomena or DIC. In each of these situations, the benefit of treatment with Nonafact should be weighed against the risk of these complications.

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 virus. Despite this, when medicines 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 or 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.

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

It is strongly recommended that every time that Nonafact 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.

After repeated treatment with Nonafact, 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.

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

4.5 Interactions with other medicinal products and other forms of interaction

No interactions of Nonafact with other medicinal products are known.

4.6 Fertility, 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 breastfeeding is not available. Therefore, factor IX should be used during pregnancy and lactation only if clearly indicated.

4.7 Effects on ability to drive and use machines

Nonafact has no influence on the ability to drive and use machines.

4.8 Undesirable effectsFand stinging at the

Hypersensitivity or allergic reactions (which may include angioedema, b infusion site, chills, flushing, generalised urticaria, headache, hives, hypo restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently in patients treated with factor IX containing products. In some case, 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 on haemophilia 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, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. During clinical trials with Nonafact conducted in previously treated patients development of inhibitors was not reported. There is no experience of the treatment of previously untreated patients with Nonafact.

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.

Nonafact contains trace amounts (< 0.1 ng mouse IgG/IU of factor IX) of the murine monoclonal antibody used in its purification. In theory, therefore, the use of Nonafact could generate antibodies to mouse protein. The clinical relevance of antibodies to mouse protein, if these do indeed arise, is not known.

For safety with respect to transmissible agents, see 4.4.

4.9 Overdose

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

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

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 a vitamin 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 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 levels of factor IX are increased, thereby enabling a temporary correction of the factor IX deficiency and correction of the bleeding tendencies.

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

5.2 Pharmacokinetic properties

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

5.3 Preclinical safety data

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

6.1

List of excipients

Powder:

Sodium chloride Sucrose Histidine.

Solvent:

Water for injections.

6.2 Incompatibilities

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

6.3 Shelf life

• 2 years

After reconstitution:

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 used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 0C, unless reconstitution/di­lution (etc) has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

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

6.5 Nature and contents of container

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

6.6 Instructions for use/and handling, and disposal

Reconstitution

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

aterial should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Sanquin

Plesmanlaan 125

NL-1066 CX Amsterdam

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/01/186/001 (500 IU)

EU/1/01/186/002 (1000 IU)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

Date of first authorisation: 3 July 2001

Renewal of authorisation: 3 July 2006