Fibrogammin P

1. Name Of The Medicinal Product

Fibrogammin^® P

Powder and solvent for solution for injection or infusion

2. Qualitative And Quantitative Composition

Active ingredient: Fibrogammin P is a purified concentrate of blood coagulation factor XIII. It is derived from human plasma, and is presented as a white powder.

Powder	68 - 135 mg
Human plasma fraction with a factor XIII activity of	250 IU
Total protein	24 - 64 mg

Excipients:

Sodium (as chloride and hydroxide): 2.78 to 4.36 mg/ml (120 to 189 mmol/L)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection or infusion.

4. Clinical Particulars

4.1 Therapeutic Indications

Congenital deficiency of Factor XIII and resultant haemorrhagic diathesis, haemorrhages and disturbances in wound healing.

4.2 Posology And Method Of Administration

Posology

1 ml is equivalent to 62.5 IU, and 100 IU are equivalent to 1.6 ml, respectively.

Important: The amount to be administered and the frequency of administration should always be orientated towards clinical efficacy in the individual case.

The following table can be used to guide dosing in bleeding episodes and surgery for adults and children:

Type of treatment	Dosage International Units [IU] per kg body weight [b.w.]	Frequency of doses / Duration of Treatment
Prophylaxis of haemorrhages	10	Approx. once a month. The interval is to be shortened if spontaneous haemorrhages develop.
Before surgical operations	Up to 35	Immediately before surgery, then the required efficacy should be maintained by repeated injections until the wound has healed completely.
Therapy	10-20	Daily, for severe haemorrhages and extensive haematomas until bleeding has stopped.

In acute bleeding episodes, especially intracranial bleedings, factor XIII must be raised to normal levels, which can be achieved by doses up to 50 IU/kg.

Due to the different pathogenesis of factor-XIII-deficiencies the data available on half-lives differ considerably. Thus, monitoring the increase in factor-XIII-activity with a factor-XIII-assay is recommended. In the case of major surgery and severe haemorrhages the aim is to obtain normal values.

The experience in children is limited.

Method of administration

Reconstitute the preparation as described in section 6.6. The preparation should be warmed to room or body temperature before administration. Slowly inject or infuse intravenously at a rate which the patient finds comfortable. The injection or infusion rate should not exceed approx. 4ml per minute.

Observe the patient for any immediate reaction. If any reaction takes place during the administration of Fibrogammin P, 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).

4.3 Contraindications

Hypersensitivity to the active ingredient or any of the excipients.

4.4 Special Warnings And Precautions For Use

If anaphylactic reactions occur (see section 4.8) the administration of Fibrogammin P should be discontinued immediately and appropriate treatment initiated. The current medical standards for shock treatment should be observed.

In the case of patients with known allergies to the product, with symptoms such as generalised urticaria, rash, a fall in blood pressure, dyspnoea, antihistamines and corticosteroids may be administered prophylactically.

In case of existing thrombosis caution should be exercised on account of the fibrin-stabilizing effect of Factor XIII. A stabilization of the thrombus might occur, resulting in increased risk of vessel occlusions.

After repeated Fibrogammin P treatment, patients should be carefully monitored for the development of inhibitors to FXIII by appropriate clinical observation and laboratory tests.

Note for diabetic patients

Fibrogammin P contains glucose (24 mg per 250 IU). When administering a dose of 10 IU/kg body weight to a patient with 75 kg body weight, a maximum of 72 mg glucose will be supplied. In cases of the maximum daily dose of 35 IU/kg body weight (assuming the same body weight), a maximum of 252 mg glucose would be supplied.

Note for patients on a low sodium diet

Fibrogammin P contains 116.6 to 183.2 mg (5.07 to 7.97 mmol) sodium per dose (bodyweight 75 kg), if the maximal daily dose (2625 IU = 42 ml) is applied. To be taken into consideration in patients on a controlled sodium diet.

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 virus HAV.

The measures taken may be of limited value against other non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).

Vaccination against hepatitis A and hepatitis B should be considered for patients in regular receipt of medicinal products derived from human blood or plasma.

It is strongly recommended that whenever Fibrogammin P is administered to a patient, the product name and batch number are recorded in order to maintain a link between the patient and the batch of the product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interactions of Fibrogammin P with other medicinal products are known so far.

4.6 Pregnancy And Lactation

The safety of Fibrogammin P for use in human pregnancy or breast-feeding has not been established in controlled clinical trials.

Experimental animal studies are insufficient to assess the safety with respect to reproduction, development of the embryo or foetus, the course of gestation and peri- and postnatal development.

The clinical use of Fibrogammin P in pregnancy did not show any negative effects on the course of gestation and the peri- or postnatal development. The efficacy of Fibrogammin P in pregnant women with congenital factor-XIII-deficiency has been described.

Therefore, Fibrogammin P should only be used if clearly needed during pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

The following adverse reactions are based on post-marketing experience.

The following standard categories of frequency are used:

Very common:

Common:

Uncommon:

Rare:

Very rare: < 1/10,000

Immune system disorders

In rare cases allergic-anaphylactic reactions, e.g. generalised urticaria, rash, hypotension, dyspnoea are observed. The treatment required depends on the nature and severity of the side effects (see section 4.4).

In very rare cases the development of inhibitors to Factor XIII may occur.

General disorders

In rare cases a rise in temperature can be observed.

For safety with respect to transmissible agents, see section 4.4.

4.9 Overdose

No cases of overdose have been reported.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antihaemorrhagics

ATC code: B02B D07

Biochemically, factor XIII acts as transglutaminase.

Factor XIII connects the amino group of lysine with glutamine via its enzymatic function (transamidase activity), thereby leading to the cross-linking of fibrin molecules. This is the final stage of blood coagulation. Fibrin cross-linking and stabilisation promote the penetration of fibroblasts and support wound healing.

5.2 Pharmacokinetic Properties

The product is administered intravenously, and is thus immediately bioavailable resulting in a plasma concentration corresponding to the applied dose.

In congenital factor-XIII-deficiency the biological half-life of Fibrogammin P was determined to be 9.2 days (median). Fibrogammin P is metabolised in the same way as is the endogenous coagulation factor XIII.

5.3 Preclinical Safety Data

Concentrate of human factor XIII as a normal constituent of the human plasma acts like the physiological factor XIII. Single dose toxicity testing revealed no adverse findings in different species even at dose levels several times higher than the recommended human dose.

Repeated dose toxicity testing is impracticable due to the development of antibodies in animal models.

To date, Fibrogammin P has not been reported to be associated with embryo-foetal toxicity, oncogenic or mutagenic potential.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Human albumin

Glucose

Sodium chloride*

Hydrochloric acid or sodium hydroxide (for pH adjustment)

*see also section 4.4

Supplied solvent: Water for Injections 4 ml

6.2 Incompatibilities

Fibrogammin P should not be mixed with other medicinal products, diluents or solvents and should be administered by a separate infusion line.

6.3 Shelf Life

3 years

Do not use after the expiry date given on the pack and container.

From a microbiological point of view, and as Fibrogammin P contains no preservative, the reconstituted product should be used immediately.

If it is not administered immediately, storage shall not exceed 8 hours at +2 to +8 °C.

6.4 Special Precautions For Storage

Store in a refrigerator (+2 to +8 °C). Do not freeze. Keep the vial in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

Vials:

Powder: 6 ml injection vial of colourless glass, sealed with a rubber stopper, an aluminium cap and a plastic disc.

Solvent (Water for Injections): 4 ml ampoule of colourless glass

Presentation:

1 vial with powder

1 ampoule with 4 ml Water for Injections

6.6 Special Precautions For Disposal And Other Handling

General instructions

Reconstitution and withdrawal must be carried out under aseptic conditions. Do not use solutions which are cloudy or contain residues (deposits/particles).

Reconstitution:

Warm both the solvent and powder in unopened vials to room or body temperature (not above 37 °C).

Take the solvent ampoule upright in your hand and shake down the solvent from the ampoule tip.

Break off the ampoule tip with thumb and forefinger. Withdraw the solvent into a syringe.

Remove the cap from the substance vial. Treat the surface of the rubber stopper with antiseptic solution and allow it to dry.

Insert the cannula of the syringe filled with the solvent into the rubber stopper of the substance vial.

The vacuum will draw the solvent automatically into the vial with the powder. Make sure that the powder is completely covered.

After complete transfer of the solvent to the substance vial gently swirl the vial until the powder is reconstituted and the solution is ready for administration. Avoid vigorous shaking causing formation of foam. A colourless, clear to slightly opalescent solution of neutral pH is obtained.

The reconstituted product should be administered immediately (see section 6.3).

Any unused solution should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

CSL Behring GmbH

Emil-von-Behring-Strasse 76

35041 Marburg

Germany

8. Marketing Authorisation Number(S)

PL 15036/0006

9. Date Of First Authorisation/Renewal Of The Authorisation

22 June 1998 / 30 October 2003

10. Date Of Revision Of The Text

21 March 2011