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SUMMARY OF PRODUCT CHARACTERISTICS
OPTIVATEâ
High Purity Factor VIII and von Willebrand Factor concentrate
1. NAME OF THE MEDICINAL PRODUCT
Optivateâ, 100 IU/mL human factor VIII, a powder for solution.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Optivate is a concentrate of human coagulation factor VIII with associated von Willebrand factorFactor (VWF) (the natural stabiliser for FVIII). There are no added proteins as stabilisers. The product is obtained from blood from screened donors. These donors are selected from the USA.
Each vial contains nominally 250 IU, 500 IU or 1000 IU of human coagulation factor VIII. One mL of Optivate contains approximately 100 IU of human coagulation factor VIII after reconstitution with when reconstituted with 2.5 mL (250 IU), 5 mL (500 IU) or 10 mL (1000 IU) of Sterilised Water for Injections, Ph.Eur..
The factor VIII potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The factor VIII specific activity of Optivate is approximately calculated as 800 IU/mg protein when VWF is discounted and approximately 43not less than 30 IU/mg protein when the presence of VWF is considered in the calculation.
The product contains approximately 172 IU VWF potency (IU) is measured according to Ristocetin Cofactor activity (VWF:RCo per mL when reconstituted with Sterilised Water for Injections as described above.
), and ELISA antigen method, compared to the International Standard for von Willebrand Factor concentrate (WHO). The specific activity ratio of OptivateFVIII for VWF antigen is approximately 751 IU:1.7 IU. The content of VWF:RCo/mg protein in Optivate is 90 – 250 IU/mL.
The VWF potency (IU) is measured according to ristocetin cofactor activity (VWF:RCo) compared to the International Standard for von Willebrand factor concentrate (WHO).
The label on each vial states the assayed amounts of factor VIII and VWF ristocetin cofactorRistocetin Cofactor activities.
For a full list of excipients, see 6.1.
3. PHARMACEUTICAL FORM
Powder for solution.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital 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.
The dosage and duration of the substitution therapy depend on the severity of the FVIII deficiency, on the location and extent of the bleeding and the patient’spatients clinical condition.
Posology
On demand treatment
The number of units of factor VIII administered is expressed in International Units (IU), 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 (IU) 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 IU factor VIII per kg body weight raises the plasma factor VIII activity by 2.2% - -2.7% of normal activity (2.2-2.7 IU/dL). The required dosage is determined using the following formula:
Required units =
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body weight (kg)
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x
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desired factor VIII rise (%) (IU/dL)
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x
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0.4
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The amount to be administered and the frequency of administration should always be orientated 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; IU/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
(%) (IU/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 to 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 resolved.
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Surgery
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Minor surgery
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 surgery
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80-100
(pre- and postoperative)
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Repeat infusion every 8 to 24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60% (IU/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 IU 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.
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.
Paediatric patients
Optivate is indicated for use in children, including those less than 6 years of age. The usual dose is 17 to 30 IU/kg. This can be given up to 3 times a week to prevent bleeding. In the clinical trials the median doses in children ≤6 years of age were 24.7 IU/kg for routine prophylaxis and 27.6 IU/kg to treat a bleed.
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 also 4.4.
Method of administration
Dissolve the preparation as described in 6.6. The product should be administered via the intravenous route at a rate not exceeding 3 mL per minute (note that increasing the rate of administration may result in side effects).
4.3If it is necessary to receive more than one vial, the contents of all the vials may be drawn up into a syringe of appropriate size. A separate sterile filter needle should be used for each vial because sterile filter needles are intended to filter the contents of a single vial of the Optivate.
Contra-indications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special warnings and special 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 and VWF. 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, standardthe current medical standards for shock-treatment for shock should be implementedobserved.
Standard measures are implemented 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 non-enveloped viruses HAV and parvovirus B19.
It is strongly recommended that every time that Optivate 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.
Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived factor VIII concentrates.
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 the 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.
Cases of recurrent inhibitor (low titre) have been observed after switching from one FVIII 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.
In general, all 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 4.8 Undesirable effects.
4.5 Interaction with other medicaments and other forms of interaction
No interactions of human coagulation factor VIII products with other medicinal products have been reportedare known.
4.6 Pregnancy and lactation
Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and lactation only if clearly indicated.
4.7 Effects on ability to drive and use machines
Optivate has no influence on the ability to drive and use machines.
4.8 Undesirable effects
The following adverse reactions have been reported from 96 patients in clinical studies. Hypersensitivity or allergic reactions (which may include angioedema, flushing, generalised urticaria, hives, hypotension, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently, and may in some cases progress to severe anaphylaxis.
Approximately 10% of patients can be expected to experience adverse reactions on long-term treatment. The following adverse reactions have been reported from 96 patients in clinical studies. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to ≤1/1000); rare (≥1/10,000 to ≤1/1,000); very rare (≤1/10,000).):
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MedDRA Standard System Organ Class
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Adverse Reactions
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Frequency
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Nervous System Disorders
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Headache
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Common
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Somnolence
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Common
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Ear and Labyrinth Disorders
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Vertigo (dizziness)
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Common
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Skin and Subcutaneous Tissue Disorders
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Rash
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Common
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Pruritus
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Common
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Musculoskeletal and Connective Tissue Disorders
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Muscle and joint stiffness
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Common
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General Disorders and Administration Site Disorders
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Infusion site erythema, rash, or pain
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Common
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Oedema peripheral
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Common
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Shivering (rigors)
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Common
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Fever (pyrexia)
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Common
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In post- marketing experience, the following additional undesirable effects have been reported: sneezing, cough, throatSneezing, Cough, Throat irritation, abdominalAbdominal pain and malaiseMalaise.
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.
Patients with haemophilia A may develop neutralising antibodies (inhibitors) 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. One previously untreated patient (PUP) has been treated in the clinical development programme. Neither he nor any of the 95 previously treated patients (PTPs) in the clinical trials has developed inhibitors. The median number of exposure days in these patients was 97 days (range 2 to 408 days).
For information on viral safety see 4.4.
4.9 Overdose
No case of overdose has been reported.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group :
Antihaemorrhagics: blood coagulation factor VIII,. ATC code: B02BD02.
The factor VIII/von Willebrand factorFactor complex consists of two molecules (factor VIII and von Willebrand factorFactor) with different physiological functions. When infused into a haemophiliac patient, factor VIII binds to von Willebrand factorFactor 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:C 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 factorFactor mediates platelet adhesion to sites of vascular injury and plays a role in platelet aggregation.
From clinical trial experience, young children using prophylactic Optivate experienced less bleeds than those only using it on demand. For doses in children see 4.2.
5.2 Pharmacokinetic properties
The pharmacokinetics of Optivate have been evaluated in 15 patients with severe haemophilia A after bolus doses of 50 IU/kg. The mean results were as follows:
Non-compartmental terminal half-life 12.4 hours
95%CI 10.94-13.83 hours
Mean Residence Time 17.5 hours
95%CI 15.99-18.92 hours
Clearance 3.1 mL/kg/h
95%CI 2.71-3.51 mL/kg/h
Area under curve (AUC0-48h) 16.1 h.IU/mL
95%CI 13.97-18.28 h.IU/mL
Area under curve (AUC0-inf) 17.31 h.IU/mL
95%CI 14.98-19.65 h.IU/mL
Volume of distribution 53.4 mL/kg
95%CI 46.2-60.52 mL/kg
Alpha half-life 2.2 hours
95%CI 1.48-2.88 hours
Beta half-life 12.6 hours
95%CI 11.33-13.92 hours
Incremental recovery 2.5 IU/dL per IU/kg
95%CI 2.22-2.74 IU/dL per IU/kg
During the clinical trials, there were 309 assessments of incremental recovery, all based on the maximum FVIII:C in the first hour (ISTH 2001). These assessments have involved 27 batches of Optivate and 70 adults with severe haemophilia A. The overall values of incremental recovery were as follows:
Mean: 2.7 IU/dL per IU/kg
95%CI: 2.53-2.80 IU/dL per IU/kg
Median: 2.6 IU/dL per IU/kg.
5.3 Preclinical safety data
The factor VIII and von Willebrand factorFactor in Optivate are normal constituents of human plasma and act in the same way as the endogenous proteins. Therefore, therefore, safety testing is not relevant.
However, an acute toxicity study and a repeated dose toxicity study in mice indicated that the Optivate formulation was not toxic, even at levels up to 20 times that likely to be used in man. In these studies, the various constituents of the product were administered to the test animals in different, greater, amounts for each excipient, compared to that in a clinical dose.
It is scientifically inappropriate to conduct genotoxicity or carcinogenicity studies with plasma coagulation factor VIII with or without its natural stabiliser, VWF.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
The reconstituted solution contains:
Sodium chloride
Sodium citrate
Calcium chloride
Polysorbate 20
Trehalose.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Only the recommended injection/infusion sets should be used because treatment failure can occur as a consequence of human plasma coagulation factor VIII adsorption to the internal surfaces of some infusion equipment.
6.3 Shelf life
Unopened (at 2°C - 25°C, in the dark) 3 years.
6.4 Special precautions for storage
Store below 25°C. Do not freeze. Protect from light.
6.5 Nature and contents of container
The product is presented as a 250 IU, 500 IU or 1000 IU presentation in Type I, Ph.Eur., glass vials. These vials are stoppered with a halobutyl rubber freeze-drying stopper under vacuum and then oversealed with a snap-off polypropylene cap and aluminium lacquered skirt.
Supplied with the product is a Transfer Device called Mix2VialTM to allow needle-free, easy and safe reconstitution of the product with the Sterilised Water for Injection, (Ph.Eur.).
6.6 Special precautions for disposal and other handling
Optivate should only be reconstituted with Water for Injections provided with the product. The 250 IU, 500 IU and 1000 IU presentations should be reconstituted using 2.5 mL, 5 mL and 10 mL Sterilised Water for Injections, Ph.Eur., respectively.
The container of Optivate and Water for Injections should be brought to between 20°C and
30°C prior to the removal of the flip-off closure from the product vial.
The Mix2VialTM Transfer Device is provided with the product for needle-free, easy and safe use.
The reconstitution is performed as follows:
Step 1: Remove the cap from the product vial and clean the top of the stopper with an alcohol swab. Repeat this step with the sterile water vial. Peel back the top of the Transfer Device package but leave the device in the package.
Step 2: Place the blue end of the Transfer Device on the water vial and push straight down until the spike penetrates the rubber stopper and snaps into place.
Remove the plastic outer packaging from the Transfer Device and discard it, taking care not to touch the exposed end of the device.
Step 3: Turn the water vial upside down with the Transfer Device still attached.
Place the clear end of the Transfer Device on the product vial and push straight down until the spike penetrates the rubber stopper and snaps into place.
Step 4: The sterile water will be pulled into the product vial by the vacuum contained within it. Gently swirl the vial to make sure the product is thoroughly mixed. Do not shake the vial. A clear or slightly pearl-like solution should be obtained, usually in about 2 to 2 ½ minutes (5 minutes maximum).
Step 5: Separate the empty water vial and blue part from the clear part by unscrewing anti-clockwise. Draw air into the syringe by pulling the plunger to the volume of water added. Connect the syringe to the white filter and push the air into the vial.
Step 6: Immediately invert the vial of solution which will be drawn into the syringe. Disconnect the filled syringe from the device. Follow normal safety practices to administer your medicine.
Note: If you have more than one vial to make up your dose, repeat Steps 1 through 6 withdrawing the solution in the vial into the same syringe.
The Transfer Device supplied with the product is sterile and cannot be used more than once. When the reconstitution process is complete, dispose of in the ‘sharps box’.
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