OCTANATE

Octanate 250 IU.

Powder and solvent for solution for injection.

Octanate 250 IUcontains nominally 250 IU human coagulation factor VIII per vial.

The product contains approximately 50 IU* per ml human coagulation factor VIII when reconstituted with the supplied solvent (5 ml for 250 IU/vial).

Produced from the plasma of human donors.

The product contains approximately ≤ 30 IU per ml von Willebrand factor (VWF:RCo).

Excipient with known effect:

This medicinal product containsless than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'

Forthe full list of excipients, see section 6.1.

*The potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The mean specific activity of Octanate is ≥100 IU/mg protein.

Powder and solvent for solution for injection.

The powder is white or pale yellow, also appearing as a friable solid.

The solvent is a clear, colourless liquid.

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

This preparation does not contain von Willebrand factor in pharmacologically effective quantities and is therefore not indicated in von Willebrand’s disease.

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

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 World Health Organisation (WHO) international 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).

On-demand treatment

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 1.5% to 2% of normal activity. The required dosage is determined using the following formula:

Required units = body weight (kg) x desired factor VIII rise (%) (IU/dl) x 0.5

The amount and frequency of administration should always be adjusted according to the clinical effectiveness in the individual patient.

In the case of the following haemorrhagic events, the factor VIII activity should not fall below the given plasma activity level (in % of normal) 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 does may be necessary.

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 the steady state equation with the measured level and the known rate of infusion.

During the course of treatment, appropriate determination of factor VIII level is advised to guide the dose to be administered and the frequency of repeated infusions. In the case of major surgical interventions in particular, a 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, demonstrating different half-lives and recoveries.

Previously untreated patients

Clinical data on the use of Octanate in previously untreated patients (PUPs) are limited. Currently available data are described in section 4.8.

Paediatric population

A clinical study which was conducted in 15 patients of 6 years of age or less did not identify any special dosage requirements for children.

Method of administration

Intravenous use.

It is recommended not to administer more than 2–3 mL per minute.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.

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

Hypersensitivity
Allergic type hypersensitivity reactions are possible with Octanate. 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 of shock should be implemented.

Inhibitors
The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication of the treatment 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 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 all patients carefully for inhibitor occurrence following any product switch.

In general, all patients treated with 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.

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 immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped virus hepatitis A virus (HAV). 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. hemolytic 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 Octanate 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.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially `sodium-free`.

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

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

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.

Octanate has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

Hypersensitivity or allergic reactions (which may include angiooedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, chest tightness, tingling, vomiting, wheezing) have been observed rarely, and may in some cases progress to severe anaphylaxis (including shock).

On rare occasions, fever has been observed.

Patients with haemophilia A may develop antibodies (inhibitors) to factor VIII. If such inhibitors occur, the condition will manifest 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).

Paediatric population

Frequency, type and severity of adverse reactions in children are the same as in adults.

Previously untreated patients

In an ongoing clinical trial in previously untreated patients (PUPs), 3 out of 39 (7.6%) PUPs treated with Octanate on-demand developed inhibitors with a titre above 5 BU. One patient developed inhibitors with a titre below 5 BU. Two cases (5.1%) were of clinical relevance; the remaining two subjects displayed inhibitors that disappeared spontaneously without an Octanate dose change. All inhibitors developed with on-demand treatment and before exposure day 50.

35 PUPs had a baseline FVIII activity < 1% and 4 PUPs had £2% FVIII:C. At the time point of the interim analysis, there were 34 patients who had already 20 or more exposure days to Octanate and 30 patients with 50 or more exposure days to Octanate. No inhibitors were observed in PUPs receiving prophylaxis with Octanate. During the study, 12 PUPs underwent 14 surgical procedures. The median age at the first exposure was 7 months (range 3 days to 67 months). The median number of exposure days in the clinical trial was 100 (range 1-553).

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

No case of overdose has been reported.

Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII

ATC-Code: B02BD02

The factor VIII/ von Willebrand factor complex consists of two molecules (FVIII and vWF) 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 results 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.

Octanate is being assessed for induction of immune tolerance induction (ITI) therapy in an ongoing observational clinical study.

In an interim analysis of the 69 patients so far treated with Octanate via ITI, 49 patients have completed the study. In the patients where the inhibitor was successfully eliminated, the monthly bleeding rates were significantly reduced.

Human plasma coagulation factor VIII (from the powder) is a normal constituent of the human plasma and acts like the endogenous factor VIII. After injection of the product, approximately two-thirds to three-quarter of the factor VIII remain in the circulation. The level of factor VIII activity reached in the plasma should be between 80% - 120% of the predicted factor VIII activity.
Plasma factor VIII activity decreases by a two-phase exponential decay. In the initial phase, distribution between the intravascular and other compartments (body fluids) occurs with a half-life of elimination from the plasma of 3 to 6 hours. In the subsequent slower phase (which probably reflects the consumption of factor VIII), the half-life varies between 8 to 20 hours, with an average of 12 hours. This corresponds to the true biological half-life.

For Octanate the following results were achieved for two pharmacokinetic studies with 10 and 14 haemophilia A patients, respectively:

AUC* = area under the curve,

MRT* = mean residence time,

SD* = standard deviation

Toxicological data available on tri-n-butylphosphate (TNBP) and polysorbate 80 (tween 80), the solvent/detergent reagents used in the SD method of viral inactivation during manufacture of Octanate, although limited for the latter, indicate that adverse effects are unlikely at the anticipated human exposures.

Even doses of several times the recommended human dosage per kilogram body weight of these reagents show no toxic effects on laboratory animals. No mutagenic potential was observed for either of the two substances.

Powder:

o Sodium citrate

o Sodium chloride

o Calcium chloride

o Glycine

Solvent: Water for injections

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

Only the provided injection or infusion sets should be used, because treatment failure can occur as a consequence of human coagulation factor VIII adsorption to the internal surface of some injection/infusion equipment.

2 years

The reconstituted solution must be used immediately andfor single useonly.

Store in a refrigerator (2°C - 8°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.

One package Octanate contains:

- Powder in a vial (type I glass), with a stopper (chlorobutyl or bromobutyl rubber), and a flip off cap

-solvent in a vial (type I glass), with a stopper (chlorobutyl or bromobutyl rubber), and a flip off cap

- one disposable syringe, transfer set Mix2Vial^TM, one injection set, and two alcohol swabs

Octapharma Limited

The Zenith Building

26 Spring Gardens

Manchester M2 1AB

United Kingdom

PA0521/012/001

Date of first authorisation: 04 June 2004

Date of last renewal: 28 July 2015

June 2016

Instructions for preparing the solution: