1. Name Of The Medicinal Product
Fanhdi®
2. Qualitative And Quantitative Composition
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 | ||||
- 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.
3. Pharmaceutical Form
Powder and solvent for solution for injection.
4. Clinical Particulars
4.1 Therapeutic Indications
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 Posology And Method Of Administration
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.
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* 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.).
4.3 Contraindications
Use of this product in patients known to be hypersensitive to any of the constituents should be avoided.
4.4 Special Warnings And Precautions For Use
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
None known.
4.6 Pregnancy And Lactation
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.
4.7 Effects On Ability To Drive And Use Machines
There is no evidence that human plasma coagulation factor VIII impairs ability to drive or to operate machines.
4.8 Undesirable Effects
- 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)
4.9 Overdose
The consequences of overdosage are not known since overdosage cases have not been reported.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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.
5.2 Pharmacokinetic Properties
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 Preclinical Safety Data
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:
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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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
- Histidine
- Albumin (human)
- Arginine
- Water for Injections (solvent)
- Fibrinogen
- Heparin
- Polyethylene glycol
- Tri-n-butyl phosphate
- Polysorbate 80
6.2 Incompatibilities
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.
6.3 Shelf Life
Fanhdi® has a shelf-life of 3 years. Not stored above 30 ºC.
6.4 Special Precautions For Storage
Do not store above 30 ºC.
Do not freeze.
Do not use after expiry date.
6.5 Nature And Contents Of Container
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.
6.6 Special Precautions For Disposal And Other Handling
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.
7. Marketing Authorisation Holder
Manufacturer and holder of licence: | Distributed by: |
Instituto Grifols, S.A. | Grifols UK Ltd. |
Can Guasch, 2 - Parets del Vallès | Byron House |
08150 Barcelona - SPAIN | Cambridge Business Park, |
Cambridge CB4 0WZ |
8. Marketing Authorisation Number(S)
Fanhdi® 25 I.U./ml | PL 12930/0002 |
Fanhdi® 50 I.U./ml | PL 12930/0004 |
Fanhdi® 100 I.U./ml (1000 I.U./10 ml, 1500 I.U./15 ml) | PL 12930/0005 |
Water for Injections | PL 4447/0016 |
9. Date Of First Authorisation/Renewal Of The Authorisation
June 2005
10. Date Of Revision Of The Text
21/08/2006
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