Mononine^® 1000, 100 IU/ml, powder and solvent for solution for injection or infusion

One vial contains powder with 1000 IU human coagulation factor IX.

After reconstitution with 10 ml of water for injections 1 ml contains:

human coagulation factor IX 100 IU/ml

The potency (IU) is determined using the European Pharmacopoeia one stage clotting test. The mean specific activity of Mononine 1000 is not less than 190 IU/mg protein.

Excipient recognized to have a known effect:

Sodium (as chloride): up to 20.3 mg

For a full list of excipients, see 6.1.

Powder and solvent for solution for injection or infusion.

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

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.

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 IU factor IX per kg body weight raises the plasma factor IX activity by 1.0 % of normal activity. The required dosage is determined using the following formula:

Required units = body weight [kg] × desired factor IX rise [% or IU/dl] × 1.0*

The amount to be administered, the method as well as the frequency of administration should always be oriented to the clinical effectiveness in the individual case. Factor IX products rarely require to be administered more than once daily when given by bolus injection.

___________________________

*reciprocal of observed recovery

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 tables 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.

For long-term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 20 to 40 IU of factor IX per kg 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.

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 section 4.4.

Method of administration

Reconstitute the product as described in section 6.6. The preparation should be warmed to room or body temperature before administration. Mononine 1000 should be administered via the intravenous route at a slow rate, so as to observe the patient for any immediate reaction.

If any reaction takes place that is thought to be related to the administration of Mononine 1000 the rate of infusion should be decreased or the infusion stopped, as required by the clinical condition of the patient (see also section 4.4).

Single intravenous injection

Perform venipuncture using the accompanying venipuncture set. Attach the syrnge to the luer end of the device.

Inject slowly intravenously at a rate comfortable to the patient (max. 2 ml/min).

Continuous infusion

Mononine 1000 should be reconstituted with water for injections as described in section 6.6. After reconstitution, Mononine 1000 can be given for continuous infusion undiluted using a syringe pump.

The potency of undiluted, reconstituted Mononine 1000 is approximately 100 IU/ml.

A diluted solution is obtained as follows:

• Dilute the reconstituted, filtered solution by transferring the appropriate quantity of Mononine to the desired volume of normal saline using aseptic technique.

• In dilutions of up to 1:10 (concentration of 10 IU factor IX/ml) activity of factor IX remains stable for up to 24 hours.

• A reduction in factor IX activity may result at higher dilutions. Factor IX activity should be monitored to maintain the desired blood level.

Example for diluting 1,000 IU of reconstituted Mononine:

• The use of polyvinylchloride (PVC) IV bags and tubing is recommended.

• Mix thoroughly and check bag for leaks.

• It is recommended to replace the bags with freshly diluted Mononine every 12-24 hours.

The recommended rate for continuous infusion with Mononine 1000 to maintain a steady state factor IX level of approximately 80% is 4 IU/kg b.w./hour, but will depend on the pharmacokinetic profile of the patient and the desired factor IX target level. In patients where the clearance of factor IX is known, the infusion rate can be calculated for the individual patient.

Rate (IU/kg b.w./hr) = Clearance (ml/hr/kg b.w.) × desired factor IX increase (IU/ml)

The safety and efficacy in children have not been studied under continuous infusion (see section 4.4). Therefore, in children and adolescents, continuous infusion of Mononine 1000 should only be considered if pre-surgical pharmacokinetic data (i.e. incremental recovery and clearance) are obtained for the calculation of the dosage and levels are carefully monitored perioperatively.

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

Known allergic reaction to mouse protein.

High risk of thrombosis or disseminated intravascular coagulation (see also 4.4).

As with any intravenous protein product, allergic type hypersensitivity reactions are possible. Mononine 1000 contains traces of mouse protein (the murine monoclonal antibody used in its purification process). While the levels of mouse protein are extremely low ( 50 ng mouse protein/100 IU), infusion of such proteins might theoretically induce hypersensitivity responses.

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

Mononine 1000 contains up to 20.3 mg sodium per 1000 IU. To be taken into consideration by patients on a controlled sodium diet.

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 thrombotic phenomena or DIC. In each of these situations, the benefit of treatment with Mononine 1000 should be weighed against the risk of these complications.

There is no safety and efficacy data for continuous application in children, particularly the potential for development of inhibitors is unknown (see section 4.2).

Virus safety

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.

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

It is strongly recommended that every time that Mononine 1000 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.

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

Little data are available regarding the use of ε-aminocaproic acid following an initial infusion of Mononine 1000 for the prevention or treatment of oral bleeding following trauma or dental procedures such as extractions.

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, factor IX should be used during pregnancy and lactation only if clearly indicated.

No effects on ability to drive and use machines have been observed.

The following adverse reactions are based on post-marketing experience as well as scientific literature. The following standard categories of frequency are used:

Renal and urinary disorders:

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

Vascular disorders:

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.

General disorders and administration site conditions:

Fever has been observed rarely.

Immune system disorders:

Hypersensitivity or allergic reactions (which may include angioedema, stinging, burning (irritation), or phlebitis at the injection/infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely 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 section 4.4).

From post-marketing experience it has been reported that patients with haemophilia B may very rarely develop neutralising 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. In a clinical study, 2 of 51 patients (4%) previously untreated patients (PUPs) developed inhibitors and, in one of these patients, this was associated with an anaphylactoid reaction on two occasions.

For information on viral safety see section 4.4.

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

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

When reconstituted as recommended (see section 6.6), the resulting solution is a clear, colourless, isotonic preparation of neutral pH, containing approximately 100 times the factor IX activity found in an equal volume of plasma.

For dosage in children of less than 6 years see section 4.2 (Method of administration).

Short term infusion of Mononine 1000 in 38 patients with haemophilia B (recovery study) revealed a mean incremental recovery of 1.71 IU/dl per IU/kg b.w. (range 0.85-4.66). Mean terminal half-life in a subgroup of 28 patients was 14.9 hours (range 7.2 to 22.7).

Pharmacokinetic data of Mononine 1000 was also determined in 12 patients (elective surgery) prior to treatment with continuous infusion of Mononine 1000.

⁺⁺ Based on a subgroup of 28 patients

⁺⁺⁺ Data from only 4 of the 12 patients. The remaining 8 patients followed a simple one-compartment model. A distribution process of Mononine is thus observed only occasionally.

Human plasma coagulation factor IX is a normal constituent of human plasma and acts like endogenous factor IX. Single dose toxicity testing is of no relevance since higher doses may result in overloading.

Repeated dose toxicity testing in animals is impracticable due to the animals developing antibodies to heterologous (human) protein.

Since clinical experience provides no hint for tumorigenic or mutagenic effects of human plasma coagulation factor IX, experimental studies, particularly in heterologous species, are not considered meaningful.

Histidine, mannitol, sodium chloride,

HCl or NaOH (in small amounts for pH adjustment)

Supplied solvent:

Water for injections

This medicinal product must not be mixed with other medicinal products, except for normal saline.

2 years.

After reconstitution, from a microbiological point of view, the reconstituted product should be used immediately. However, the physico-chemical stability has been demonstrated for 24 hours at up to max. +25 °C.

After dilution (up to 1:10) of the reconstituted Mononine 1000 solution, stability has been shown for up to 24 hours.

Store in a refrigerator (2 ºC - 8 ºC). Do not freeze. Keep the vial in the outer carton.

During its shelf-life, the product (when kept in its outer carton) may be stored at ambient room temperature (up to +25 °C) for up to 1 month without being refrigerated again during this period. The date of transfer to room temperature and the end of the 1-month period should be recorded on the outer carton. At the end of this period the product has to be used or discarded.

Immediate containers

1000 IU of powder and 10 ml of solvent in vials (Type I glass) with stoppers.

Presentations

One pack with 1000 IU containing:

1 vial with powder

1 vial with 10 ml water for injections

One device pack containing:

- 1 filter transfer device 20/13

- 1 disposable 10 ml syringe

- 1 venipuncture set

- 2 alcohol swabs

- 1 non-sterile plaster

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

Method of administration

General instructions

– Reconstitution and withdrawal must be carried out under aseptic conditions.

– Usually the solution is clear or slightly opalescent. Reconstituted product should be inspected visually for particulate matter and discoloration after filtering/withdrawal (see below) and prior to administration. Do not use solutions which are cloudy or contain residues (deposits/particles).

Reconstitution

Bring the solvent to room temperature. Ensure powder and solvent vial flip caps are removed and the stoppers are treated with an aseptic solution and allowed to dry prior to opening the Mix2Vial package.

Withdrawal and application

Administer immediately by slow intravenous injection or infusion (see 4.2 “Method of administration”)

CSL Behring UK Limited

Hayworth House, Market Place

Haywards Heath

West Sussex RH16 1DB

UK

PL 00231/0099

04 February 1993 / 17 January 2008

21 September 2011