OPTIVATE 250 IU 500 IU 1000 IU POWDER AND SOLVENT FOR SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Optivate250 IU powder and solvent for solution for injection

Optivate 500 IU powder and solvent for solution for injection

Optivate 1000 IU powder and solvent for solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

3   PHARMACEUTICAL FORM

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).

Optivate can be used for all age groups.

4.2 Posology and method of administration

Treatment should be under the supervision of a physician experienced in the treatment of haemophilia.

Treatment monitoring

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. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries. Dose based on body weight may require adjustment in underweight or overweight patients.

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.

When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor VIII activity in patients’ blood samples, plasma factor VIII activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. Also there can be significant discrepancies between assay results obtained by aPTT-based one stage clotting assay and the chromogenic assay according to Ph. Eur. This is of importance particularly when changing the laboratory and/or reagents used in the assay.

Posology

The dose 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.

The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current WHO concentrate standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or preferably in International Units (relative to an International Standard for factor VIII in plasma).

One IU of factor VIII activity is equivalent to that quantity of factor VIII in 1 ml of normal human plasma.

On demand treatment

The calculation of the required dose 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 = body weight (kg) x desired factor VIII rise (%) or (IU/dl) x 0.4

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 or IU/dl) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:

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.

Continuous infusion

Prior to surgery, a pharmacokinetic analysis should be performed to obtain an estimate of clearance.

The initial infusion rate can be calculated as follows:

Clearance x desired steady state level = infusion rate (IU/kg/hr).

After the initial 24 hours of continuous infusion, the clearance should be calculated again every day using steady state equation with the measured level and the known rate of infusion.

Paediatric population

Children under 6 years of age

The recommended 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.

Children over 6 years of age

There are very limited data on the use of Optivate in children aged 6 to 12 years.

Method of administration

Intravenous use.

Optivate 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). For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Traceability

In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hypersensitivity

Allergic type hypersensitivity reactions are possible with Optivate. The product contains traces of human proteins other than factor VIII. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.

In case of shock, standard medical treatment for shock should be implemented.

Inhibitors

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 severity of the disease as well as the exposure to factor VIII, this risk being highest within the first 50 exposure days but continues throughout life although the risk is uncommon.

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre posing less of a risk of insufficient clinical response than high titre inhibitors.

In general, all patients treated with human coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed. 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 haemophilia and factor VIII inhibitors.

Cardiovascular events

In patients with existing cardiovascular risk factors, substitution therapy with factor VIII may increase the cardiovascular ris­k.

Catheter-related complications

If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.

Transmissible agents

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 human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped hepatitis A virus. The measures taken may be of limited value against 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).

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma derived factor VIII products.

It is strongly recommended that every time 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 (see section 4.8).

Paediatric population

The listed warnings and precautions apply both to adults and children.

4.5 Interaction with other medicinal products and other forms of interaction

No interactions of human coagulation factor VIII products with other medicinal products have been reported.

4.6 Fertility, 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

Summary of the safety profile

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 rarely and may in some cases progress to severe anaphylaxis (including shock).

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including Optivate. If such inhibitors occur, the condition may manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.

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

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).

Frequencies have been evaluated according to the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). The table lists adverse reactions reported from 96 patients in clinical studies. Approximately 10% of patients can be expected to experience adverse reactions on long-term treatment.

* Frequency is based on studies with all factor VIII products which included patients with severe haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients.

In post-marketing experience, the following additional undesirable effects have been reported: sneezing, cough, throat irritation, abdominal pain and malaise.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

No symptoms of overdose with human coagulation factor VIII have been reported.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: antihemorrhagics, blood coagulation factor VIII, ATC code: B02BD02.

Mechanism of action

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: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.

Of note, annualised bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.

In addition to its role as a factor VIII protecting protein, von Willebrand factor mediates platelet adhesion to sites of vascular injury and plays a role in platelet aggregation.

Paediatric population

From clinical trial experience, young children using prophylactic Optivate experienced less bleeds than those only using it on demand. For doses in children see section 4.2.

5.2 Pharmacokinetic properties

The pharmacokinetics of Optivate have been evaluated in 15 patients (>12 years old) with severe haemophilia A (<2% activity) after bolus doses of 50 IU/kg. The results are presented in the table below:

CI = Confidence Interval

Paediatric population

Pharmacokinetic data are not available in children younger than 12 years old.

5.3 Preclinical safety data

The factor VIII and von Willebrand factor in Optivate are normal constituents of human plasma and act in the same way as the endogenous proteins, therefore, safety testing is not relevant.

However, an acute toxicity study and a repeated dose toxicity study in the mouse indicated that the Optivateformulation 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, von Willebrand factor.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder

Sodium chloride

Sodium citrate

Calcium chloride

Polysorbate 20

Trehalose

Sodium Hydroxide (for pH-adjustment)

Hydrochloric Acid (for pH-adjustment)

Solvent

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Only the provided 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

3 years.

After reconstitution, chemical and physical in-use stability has been demonstrated for 1 hour up to 25°C.

From a microbiological point of view, unless the method of opening/recon­stitution precludes the risk of microbial contamination, the reconstituted medicinal 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 should not be longer that 1 hour up to 25°C.

6.4 Special precautions for storage

Do not store above 25°C.

Do not freeze.

Keep the vials in the outer carton in order to protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Optivate 250 IU powder and solvent for solution for injection

– 250 IU powder in a 10 ml vial (type 1 glass) with a stopper (halobutyl rubber), with an overseal (aluminium) and tamper evident flip-off cap (polypropylene)

– 2.5 ml solvent in a 2.5 ml vial (type 1 glass) for reconstitution

– One Mix2Vial™ transfer device

Optivate 500 IU powder and solvent for solution for injection

– 500 IU powder in a 10 ml vial (type 1 glass) with a stopper (halobutyl rubber), with an overseal (aluminium) and tamper evident flip-off cap (polypropylene)

– 5 ml solvent in a 5 ml vial (type 1 glass) for reconstitution

– One Mix2Vial™ transfer device

Optivate 1000 IU powder and solvent for solution for injection

– 1000 IU powder in a 30 ml vial (type 1 glass) with a stopper (halobutyl rubber), with an overseal (aluminium) and tamper evident flip-off cap (polypropylene)

– 10 ml solvent in a 10 ml vial (type 1 glass) for reconstitution

– One Mix2Vial™ transfer device

Not all pack sizes may be marketed.

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 water for injections, respectively (see diagram on next page).

The containers of Optivate and water for injections should be brought to between 20°C and 30°C prior to the removal of the flip-off cap from the product vial.

Reconstituted medicinal product should be inspected visually for particulate matter and discolouration prior to administration. The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. Use the product immediately after reconstitution or within 1 hour.

Any unused product or waste material should be disposed of in accordance with local requirements.

tep 1

Remove the cap from the product vial and clean the top of the stopper with an alcohol swab.

Repeat this step with the water vial.

Peel back the top of the Mix2Vial™ transfer device package but leave the device in the package.

ep 2

Place the blue end of the Mix2Vial™ 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 Mix2Vial™ transfer device and discard it, taking care not to touch the exposed end of the device.

t–—1-----------------------------------------

tep 3

Turn the water vial upside down with the device still attached.

Place the clear end of the Mix2Vial™ transfer device on the product vial and push straight down until the spike penetrates the rubber stopper and snaps into place.

"tep 4

The 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 % minutes (5 minutes maximum).

tep 6

Immediately invert the vial of solution which will be drawn into the syringe.

Disconnect the filled syringe from the Mix2Vial™ transfer device.

The product is now ready for administration. Follow the normal safety practices for administration. Use the product immediately after reconstitution, the product must not be stored.

Note: If you have more than one vial to make up your dose, repeat Steps 1 to 6 withdrawing the solution in the vial into the same syringe.

The Mix2Vial™ transfer device supplied with the product is sterile and cannot be used more than once.

Bio Products Laboratory Limited

Dagger Lane, Elstree, Hertfordshire, WD6 3BX

United Kingdom

Email: medinfo@bpl.co­.uk

8 MARKETING AUTHORISATION NUMBER(S)

PL 08801/0051

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 10 December 2004

Date of latest renewal: 21 January 2018