| 3. PHARMACEUTICAL FORM
Powder and solvent for solution for injection.
Vial containing white or pale yellow powder and syringe with Water for Injections (solvent).
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Fanhdi® is indicated for the treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).
Despite the von Willebrand factor content and functionality of this product there are no data from clinical trials supporting use in von Willebrand disease.
This product may be used in the management of acquired factor VIII deficiency.
4.2 Posology and method of administration
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 VIII deficiency, on the location and extent of the bleeding and on the patient’s clinical condition.
On demand treatment
The number of units of factor VIII administered is expressed in International Units (I.U.), which are related to the current WHO standard for factor VIII products. Factor VIII 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 VIII in plasma).
One International Unit (I.U.) of factor VIII activity is equivalent to that quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage of factor VIII is based on the empirical finding that 1 International Unit (I.U.) factor VIII per kg body weight raises the plasma factor VIII activity by 2.1 ± 0.4% of normal activity. The required dosage is determined using the following formula:
Required units = body weight (kg) ´ desired factor VIII rise (%) (I.U./dl) ´ 0.5
The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.
In the case of the following haemorrhagic events, the factor VIII activity should not fall below the given plasma activity level (in % of normal or I.U./dl) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:
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Degree of haemorrhage/ Type of surgical procedure
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Factor VIII level required (%) (I.U./dl)
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Frequency of doses (hours)/
Duration of therapy (days)
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Haemorrhage
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Early haemarthrosis, muscle bleeding or oral bleeding
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20 ‑ 40
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Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.
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More extensive haemarthrosis, muscle bleeding or haematoma
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30 ‑ 60
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Repeat infusion every 12‑24 hours for 3‑4 days or more until pain and acute disability are resolved.
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Life threatening haemorrhages
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60 ‑ 100
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Repeat infusion every 8 to 24 hours until threat is resolved.
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Surgery
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Minor
including tooth extraction
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30 ‑ 60
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Every 24 hours, at least 1 day, until healing is achieved.
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Major
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80 ‑ 100
(pre-and postoperative)
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Repeat infusion every 8‑24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60% (I.U./dl).
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Prophylaxis
For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 I.U. of factor VIII per kg body weight at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.
Continuous infusion
During the course of treatment, appropriate determination of factor VIII 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 VIII activity) is indispensable. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives.
Patients should be monitored for the development of factor VIII inhibitors. If the expected factor VIII 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 VIII inhibitor is present. In patients with high levels of inhibitor, factor VIII 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 section 4.4.
Paediatric population
There are insufficient data from clinical trials to recommend the use of Fanhdi® in children less than 6 years of age.
As the posology is adjusted to the clinical outcome of the above mentioned conditions, the posology in children, by body weight, is not considered to be different to that of adults.
Method of administration
Dissolve the preparation as described in section 6.6. The product should be administered via the intravenous route. Fanhdi® should be administered at a rate of no more than 10 ml/min.
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 human proteins other than factor VIII. 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.
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. The measures taken may be of limited value against non-enveloped viruses such as HAV and 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).
The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per ml of plasma using Nijmegen’s modified assay. The risk of developing inhibitors is correlated to the exposure to anti-haemophilic factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days. Patients treated with human coagulation factor VIII should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. See also section 4.8.
Cases of recurrent inhibitor (low titre) have been observed after switching from one factor VIII product to another in previously treated patients with more than 100 exposure days who have a previous history of inhibitor development. Therefore, it is recommended to monitor patients carefully for inhibitor occurrence following any product switch.
Appropriate vaccination (hepatitis A and B) should be considered for patients in regular receipt of human plasma-derived factor VIII products.
It is strongly recommended that every time that Fanhdi® 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.
4.8 Undesirable effects
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently, and may in some cases progress to severe anaphylaxis (including shock).
On rare occasions, fever has been observed.
The adverse drug reactions reported are summarised and categorised according to the MedDRA system organ class in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing of seriousness. Frequency has been determined using the following criteria:
- very common: >1/10 infusions
- common: >1/100 to <1/10 infusions
- uncommon: >1/1,000 to <1/100 infusions
- rare: >1/10,000 to <1/1,000 infusions
- very rare: <1/10,000, not known (cannot be estimated from the available data.)
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System Organ Class
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Body System Preferred Term
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ADR frequency
evaluation
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General disorders and administration site conditions
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Pyrexia
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Rare
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Patients with haemophilia A may develop neutralising antibodies to factor VIII. 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.
There is no experience in previously untreated patients.
For information on transmissible agents’ safety, see section 4.4.
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Antihaemorrhagics: blood coagulation factor VIII. ATC code: B02BD02.
In Fanhdi®, factor VIII is presented as a complex with von Willebrand factor.
The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions.
When infused into a haemophiliac patient, factor VIII binds to von Willebrand factor in the patient’s circulation.
Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed.
Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII 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 VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
In addition to its role as a factor VIII protecting protein, von Willebrand mediates platelet adhesion to sites of vascular injury and plays a role in platelet aggregation.
There are insufficient data from clinical trials in children less than 6 years of age.
6.6 Special precautions for disposal and handling
Do not use after the expiry date shown on the label.
Left-over product must never be kept for later use, nor stored in a refrigerator.
To prepare the solution:
1. Warm the vial and syringe but not above 30ºC.
2. Attach plunger to syringe containing diluent.
3. Remove filter from packaging. Remove cap from syringe tip and attach syringe to filter.
4. Remove vial adaptor from packaging and attach to syringe and filter.
5. Remove cap from vial and wipe stopper with swabs provided.
6. Pierce vial stopper with adaptor needle.
7. Transfer all diluent from syringe to vial.
8. Gently shake vial until all product is dissolved. As with other parenteral solutions, do not use if product is not properly dissolved or particles are visible.
9. Briefly separate the syringe/filter from vial/adaptor, to release the vacuum.
10. Invert vial and aspirate solution into syringe.
11. Prepare injection site, separate syringe and inject product using the butterfly needle provided. Injection rate should be 3 ml/min into a vein and never more than 10 ml/min to avoid vasomotor reactions.
Do not re-use administration sets.
Any unused product or waste material should be disposed of in accordance with local requirements.
The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits.
Reconstituted products should be inspected visually for particulate matter and discolouration prior to administration.
10. DATE OF REVISION OF THE TEXT
October 2011
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