Fanhdi^®

2.1. Qualitative composition

Fanhdi^® is a high purity, solvent-detergent and heat-treated, human coagulation factor VIII, Ph. Eur.

2.2. Quantitative composition

Lyophilised product

- Active ingredient:

Factor VIII	250 I.U.	500 I.U.	1000 I.U.	1500 I.U.
(Total proteins	100 mg	100 mg	100 mg	150 mg)
- Other ingredients:
Histidine	40 mg	40 mg	40 mg	60 mg
Human albumin	50 mg	50 mg	50 mg	75 mg
Arginine	175 mg	175 mg	175 mg	263 mg
Solvent (separate pre-filled syringe)
Water for Injections (Ph. Eur.)	10 ml	10 ml	10 ml	15 ml

The final product has a specific activity of at least 2.5 to 10 I.U./mg of protein depending on potency (250, 500, 1000 or 1500 I.U.).

The specific activity excluding the natural stabiliser (vWF) and added albumin is greater than 1000 I.U./mg of protein.

Powder and solvent for solution for injection.

Fanhdi^® is indicated for the prevention and control of bleeding in patients with moderate or severe factor VIII deficiency due to classical haemophilia A.

Despite the von Willebrand factor content and functionality of this product there are no data from clinical trials supporting use in von Willebrand disease.

4.2.1. Posology

The dose and duration of treatment with Fanhdi^® must be adjusted according to the needs of the individual patient.

The required dosage may be estimated using the following formula:

Number of factor VIII units required (I.U.) = Body weight (kg) x Desired factor VIII rise (%) x 0.5

This calculation is based on the empirical finding that 1 I.U. of factor VIII per kg body weight raises the plasma factor VIII activity approximately 2% (i.e. 0.5 I.U./kg are required for a 1% increase in the plasma factor VIII level).

The patient's plasma factor VIII levels should be determined and monitored during treatment with Fanhdi^®. This is particularly important in the case of surgical procedures.

* For dental and oral bleeding a single dose of Fanhdi^® should be administered to elevate the plasma factor VIII activity to 40 - 50%. Tranexamic acid may be administered in addition. Further doses of Fanhdi^® should only be given if bleeding persists.

Under certain circumstances larger amounts than those calculated will be required, especially for the initial dose.

Patients with inhibitors:

If plasma factor VIII does not reach the expected levels or if the bleeding cannot be controlled after the administration of an adequate dose, the presence of inhibitors should be suspected.

Haemophiliacs with antibodies against factor VIII (inhibitors) need specific therapy. Patients with low titre inhibitors may continue treatment with factor VIII concentrates provided that their inhibitor levels are monitored. Immunetolerance can be achieved by treatment with human plasma coagulation factor VIII concentrate.

Prophylaxis:

For long-term prophylaxis against bleeding in patients with severe hemophilia A, Fanhdi^® should be administered at doses of 10 to 50 I.U./kg at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

4.2.2. Method of administration

The product should be warmed (not above 30 ºC) before administration.

Fanhdi^® is intended for intravenous administration only. Fanhdi^® may be administered at a rate of no more than 10 ml/minute. (For full details of reconstitution and use refer to section 6.6.).

Use of this product in patients known to be hypersensitive to any of the constituents should be avoided.

If allergic or anaphylactic reactions occur, administration should be stopped immediately (the current specific guidelines of shock therapy should be followed).

After repeated treatment with human plasma coagulation factor VIII, the level of inhibitor in plasma should be determined.

When medicinal products prepared from human blood or plasma are administered, infectious diseases due to the transmission of infective agents cannot be totally excluded. This also applies to pathogens of hitherto unknown nature. The risk of transmission of infective agents is however reduced by:

- selection of donors by a medical interview and screening of donations for the three major pathogenic viruses HIV, HCV and HBV

- testing of mini-pools and manufacturing pools for HBsAg, HIV and HCV antibodies and HCV-RNA by PCR

- removal/inactivation procedures included in the production process that have been validated using model viruses and are considered effective for HIV, HCV and HBV

The viral removal/inactivation procedures may be of limited value against non-enveloped viruses such as Hepatitis A virus or parvovirus B19 and other transmissible infectious agents.

The plasma used in the manufacture of this product has been collected from remunerated US donors.

Vaccination guidelines for patients treated with blood or human plasma derivatives must be taken into consideration in all the patients receiving Fanhdi^®.

Patients receiving factor VIII concentrates should be vaccinated against Hepatitis A and B.

None known.

The safety of human coagulation factor VIII for use in human pregnancy has not been established in controlled clinical trials.

Studies carried out in animal models are not sufficient to assess safety with respect to reproduction, development of the embryo or foetus, the course of gestation and peri- and postnatal development.

Therefore, factor VIII concentrates should only be used if clearly needed during pregnancy and lactation.

There is no evidence that human plasma coagulation factor VIII impairs ability to drive or to operate machines.

- Allergic or anaphylactic reactions are observed in rare cases.

- Increase in body temperature is observed in rare cases.

- Development of antibodies to factor VIII (inhibitors)

- Although the isoagglutinin content is very low, there is a risk of intravascular haemolysis.

- The transmission of infectious agents cannot be totally excluded (see item 4.4)

The consequences of overdosage are not known since overdosage cases have not been reported.

FVIII:C is responsible for the coagulation activity. As a factor IX cofactor, it accelerates the conversion of factor X into activated factor X.

Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin in such a way that a clot can be formed.

The FVIII:C activity is greatly reduced in patients with haemophilia A and, therefore, substitution therapy is necessary.

Plasma factor VIII activity decreases by a two-phase exponential decay.

The half-life of Fanhdi^® obtained in the clinical trial carried out with this product is 14.18 ± 2.55 hours and the "in vivo" recovery is 105.5 ± 18.5%, which is equivalent to approximately 0.021 ± 0.004 I.U./ml per I.U./kg administered (determinations performed following chromogenic method).

5.3.1. Viral safety

The process to manufacture Fanhdi^® has been validated for viral inactivation / removal, using HIV and model viruses for enveloped and non-enveloped viruses. Two specific steps designed to inactivate potential contaminating viruses, consisting of a treatment with tri-n-butyl phosphate (TNBP) and polysorbate and a heat treatment for 72 - 74 h at 81 ± 1 ºC, were studied.

The next table summarises the reduction factors obtained per each step and virus assayed:

Between brackets: time to absence of residual infectivity / n.d. not determined

5.3.2. Toxicological properties

Human plasma coagulation factor VIII (from the concentrate) is a normal constituent of the human plasma and acts like the endogenous factor VIII.

Single dose toxicity testing is of no relevance since higher doses result in overloading.

Repeated dose toxicity testing in animals is impracticable due to interference with developing antibodies to heterologous protein.

Even doses of several times the recommended human dosage per kilogram body weight show no toxic effects on laboratory animals.

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

- Histidine

- Albumin (human)

- Arginine

- Water for Injections (solvent)

- Fibrinogen

- Heparin

- Polyethylene glycol

- Tri-n-butyl phosphate

- Polysorbate 80

Fanhdi^® should not be mixed with any other drugs.

Use only injection/infusion sets suitable for factor VIII concentrate administration because treatment may fail as a consequence of adsorption to the internal surface of some infusion equipment.

Fanhdi^® has a shelf-life of 3 years. Not stored above 30 ºC.

Do not store above 30 ºC.

Do not freeze.

Do not use after expiry date.

Fanhdi^® is supplied in Type II glass vials containing 250, 500, 1000 or 1500 I.U. of FVIII (lyophilised) and type I glass syringes containing 10 ml of Water for Injections (solvent) for the 250, 500 and 1000 I.U. presentations and 15 ml of Water for Injections for the 1500 I.U. presentation. The accessories supplied with Fanhdi^® for reconstitution and administration of the product are: vial adaptor, filter, butterfly needle and two alcohol swabs.

Do not use after the expiry date shown on the vial label. Chemical and physical in-use stability has been demonstrated for 12 hours at 25 °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 °C, unless reconstitution has taken place in controlled and validated aseptic conditions. Left-over product must never be stored for later use, nor stored in a refrigerator.

Solution preparation:

1. Warm the vial and syringe but not above 30 ºC.

2. Attach the plastic plunger to the syringe containing diluent.

3. Remove the filter from its packaging. Remove the grey rubber cap from the syringe tip and then attach the syringe to the filter.

4. Remove the vial adaptor from its packaging. Attach the vial adaptor to the syringe-filter assembly.

5. Remove the plastic flip-top cap from the concentrate vial and wipe the exposed rubber with the antiseptic wipe provided.

6. Place the syringe/filter/adaptor assembly over the top of the concentrate vial and pierce the stopper with the adaptor needle.

7. Transfer all the Water for Injections into the concentrate vial by depressing the syringe plunger.

8. Gently swirl the vial until all the concentrate has dissolved. As with other parenteral solutions, do not use the solution if it is not properly dissolved or particles are visible.

9. Briefly separate the syringe/filter and vial/adaptor assemblies to release any vacuum.

10. Invert the concentrate vial and draw-up the solution through the filter into the syringe.

11. Prepare the injection site, separate the filter/vial adaptor from the syringe. Inject the solution intravenously using the butterfly needle provided or a sterile needle at a rate of 3 ml/minute. The administration rate should never be more than 10 ml/minute to avoid vasomotor reactions.

Do not re-use the administration sets.

June 2005

21/08/2006