INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
HAEMOSOLVATE FACTOR VIII 300 IU (POWDER FOR INJECTION)
HAEMOSOLVATE FACTOR VIII 500 IU (POWDER FOR INJECTION)

REGISTRATION NUMBER
300 IU : 31/30.3/392
500 IU : Y/30.3/292

PROPRIETARY NAME
(and dosage form):

HAEMOSOLVATE FACTOR VIII 300 IU (POWDER FOR INJECTION)
HAEMOSOLVATE FACTOR VIII 500 IU (POWDER FOR INJECTION)

DESCRIPTIVE NAME OF MEDICINE
Human Factor VIII concentrate.

PHARMACOLOGICAL CLASSIFICATION
A 30.3 Biologicals (Blood Fractions).

SCHEDULING STATUS
S4

COMPOSITION
This lyophilised concentrate, with a high specific factor VIII (factor VIII:C) and von Willebrands factor (factor VIII:vWF) activity, is prepared from pooled fresh plasma donated by healthy non-remunerated blood donors. Each unit of plasma has been individually tested and found non-reactive for hepatitis B surface antigen, antibodies to the hepatitis C virus and antibodies to the human immunodeficiency viruses, HIV-1 and HIV-2, using approved methods.
To reduce the risk of transmission of infective agents, selection of donors and donations by suitable measures is performed and removal and/or inactivation procedures are included in the production process. The manufacturing method includes a process of solvent detergent treatment developed to inactivate lipid enveloped viruses. The efficacy of this process has been tested against hepatitis B, non-A, non-B hepatitis and HIV.
300 IU: When each vial of the product is reconstituted with the 10 mL water for injection, the solution (per vial) will contain factor VIII:C - 300 IU; factor VIII:vWF - > 300 IU; sucrose - 0,15 g; protein - not more than 0,16 g, of which not more than 80% is fibrinogen.
500 IU: When each vial of the product is reconstituted with the 10 mL water for injection, the solution (per vial) will contain factor VIII:C - 500 IU; factor VIII:vWF - >500 IU; sucrose - 0,15 g; protein - not more than 0,25 g, of which not more than 80% is fibrinogen.

IDENTIFICATION
Lyophilised powder: a white or pale yellow friable powder or crystalline shell or plug.
Reconstituted solution: colourless, slightly opalescent solution, which may exhibit slight flocculation.

PHARMACOLOGICAL ACTION OF THE MEDICINE
Factor VIII is an endogenous glycoprotein necessary for blood clotting and hemostasis. It is a cofactor necessary for factor IX to activate factor X in the intrinsic pathway. In haemophilia A there is a deficiency of this clotting factor. The average normal plasma activity of factor VIII is designated 100% and a factor VIII concentration of 25% of normal is required for hemostasis. Patients with severe haemophilia have a factor VIII concentration of less than 1% of normal and frequently experience bleeding even in the absence of trauma. Patients with factor VIII concentrations between 1 and 5% (moderate haemophilia) experience less bleeding and patients with a factor VIII concentration greater than 5% (mild haemophilia) usually experience bleeding only after obvious trauma. The administration of factor VIII temporarily replaces the missing clotting factor to correct or prevent bleeding episodes.
Von Willebrands disease is characterised by abnormalities of von Willebrands factor (vWF), a large multimeric molecule which is bound to factor VIII. von Willebrands factor is necessary for platelet adhesion to subendothelial tissue. Due to low level of the carrier protein, vWF, factor VIII levels are also diminished.

Pharmacokinetics:
Factor VIII is immediately and completely bioavailable in the recipients circulation after intravenous administration. The half-life of factor VIII varies between 8 and 20 hours, with an average of 12 hours.

INDICATIONS
Treatment and prophylaxis of coagulation defects caused by congenital or acquired Factor VIII deficiency:

	Haemophilia A;
	Acquired or congenital Factor VIII deficiency with Factor VIII inhibitor (refer to Patient Monitoring - Detection and quantification of inhibitors);
	von Willebrands disease with Factor VIII deficiency.

CONTRA-INDICATIONS
Factor VIII concentrate should not be used to correct factor IX deficiency (haemophilia B, Christmas disease).
Do not use unless a factor VIII deficiency has been verified.
This product should not be the only product used for the treatment of dissemiated intravascular coagulation (DIC).
Severe allergic reaction to Haemosolvate Factor VIII.

DOSAGE AND DIRECTIONS FOR USE
Warnings:
This preparation must be administered slowly and intravenously.
Measures to treat anaphylaxis, including adrenalin and corticosteroids, must be at hand when administering Haemosolvate Factor VIII.
If a gel forms on reconstitution, the preparation must not be used. Do not give concomitantly with other medicines.
General dosing information:
Dissolve each vial of the preparation before use by adding 10 mL water for injection (see reconstitution procedure).
Individualised dosage:
The dosage and duration of treatment is based on the patient’s body mass, circulating antibody concentration, type of haemorrhage, location of bleed, type of surgery to be performed and clinical picture.
Patient monitoring:
The following may be useful in patient monitoring to determine the dosage required:
Detection and quantification of inhibitors (antibodies to factor VIII):
This predicts whether or not the patient will respond to treatment. Patients with low antibody concentrations can be managed by using increased doses of factor VIII to complex with and thereby inactivate the antibodies. However, patients with high antibody concentrations, are not likely to respond, and specific therapy is necessary.
Plasma factor VIII determination:
To assure that adequate factor VIII concentrations have been achieved and are maintained.
Determination of the dosage:
One international unit of factor VIII activity is approximately equal to the factor VIII activity of 1 mL of fresh plasma. The calculation of the required dosage of factor VIII is based on the finding that administration of one IU of factor VIII per kg body mass, results in a ± 2% increase in the factor VIII plasma concentration. The following formula may be used as a guide to calculate the required dose:
Required Units = body mass (kg) x 0,5 x desired Factor VIII increase (% of normal).
The amount to be administered and the frequency of administration should always be oriented towards clinical efficacy and therefore the recommended dosage regimes must be used as a guideline for therapy only. Longer or shorter periods and higher or lower levels of replacement therapy may be necessary.

PROPHYLAXIS OF HAEMORRHAGE:
The aim is to keep factor VIII trough levels above 1%. Dosages and dosage intervals range from 10 to 50 IU/kg intravenously every two to three days.

TREATMENT OF HAEMORRHAGE:

Haemorrhagic event	Therapeutically necessary plasma level of Factor VIII activity	Period during which it is necessary to maintain the therapeutic plasma level of Factor VIII activity
Mild haemorrhage Haemorrhage into joints	30%	At least 1 day, depending on the severity of the haemorrhage
Moderate haemorrhage Haemorrhage into muscles Mild trauma capitis Haemorrhages in the oral cavity	40 - 50%	3-4 days or until adequate wound healing
Severe, life-threatening haemorrhage Gastro-intestinal bleeding Intracranial, intra-abdominal or intra-thorasic haemorrhagic Fractures	60 - 100%	During 7 days, then therapy for at least another 7 days

PREVENTION OF BLEEDING DURING AND FOLLOWING SURGICAL PROCEDURES:
Replacement therapy must be initiated one hour prior to the procedure. The factor VIII level must be maintained high enough to prevent haemorrhage and promote epitheliasation until healing is complete and sutures are removed. Concurrent antifibrinolytic therapy to prevent or decrease bleeding during and following surgery may be required.

Haemorrhagic event	Therapeutically necessary plasma level of Factor VIII activity	Period during which it is necessary to maintain the therapeutic plasma level of Factor VIII activity
Tooth extraction (concurrent antifibrinolytic therapy) Minor/Medium operations	40 - 50%	3-4 days or until adequate wound healing
Major operations	60 - 100 %	During 7 days, then therapy for at least another 7 days

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.

VON WILLEBRANDS DISEASE: TREATMENT OF BLEEDING COMPLICATIONS AND SURGICAL INTERVENTIONS:
The principles of therapy are the same as for haemophilia A patient.

PAEDIATRIC USE: Dose is calculated according to body mass. Refer adult dose.

RECONSTITUTION:
USE ONLY THE INJECTION/INFUSION SET SUPPLIED AS HAEMOSOLVATE FACTOR VIII MUST BE ADMINISTERED VIA PLASTIC SYRINGES AND FILTERED BEFORE USE

1.	Remove the plastic cap from the stopper of the product vial and swab the exposed rubber stopper with a suitable anti-bacterial agent.
2.	Attach the FILTER NEEDLE (short metal needle) to the syringe. This must remain attached until just before infusion.
3.	Open the diluent and draw up 10 mL of water for injection. Insert the filter needle, with syringe attached, through the stopper of the product vial.
4.	The vacuum will draw the diluent into the vial. Rotate the vial to ensure complete wetting of the powder. Do not use the product if no vacuum is present.
5.	Gently swirl the vial until the powder is dissolved. Do not shake and avoid foaming. Reconstitution process should take 30 minutes at the most. Do not use if solution is         turbid or contains particulate matter or if a gel forms after reconstitution.
6.	When the solution is ready for administration, after complete dissolution, pierce the stopper with the AIR VENT needle to release the remaining vacuum in the vial. Remove and discard air vent needle.
7.	Repeat the reconstitution process if more than one vial is used.
8.	Withdraw the contents of the vial/s into the syringe.
9.	Remove the syringe and the filter needle from the vial/s. Invert the syringe, expel any air, then remove and discard the filter needle.
10.	Attach the BUTTERFLY NEEDLE to the syringe.
11.	Administer the solution as soon as possible after reconstitution but not more than three hours after reconstitution, as a slow intravenous infusion over at least 2 minutes.
12.	Discard any unused solution.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side effects may include febrile reactions, urticaria, angioedema, flushing, nausea, headache, light-headedness, and visual disturbances.
Inhibitor antibodies may develop in specific patients, which neutralizes the procoagulant activity of factor VIII and complicates replacement therapy.
Transmission of infective agents, specifically non-enveloped viruses , cannot be totally excluded, therefore patients should be vaccinated against Hepatitis A and B.
Allergic reactions or anaphylaxis may occur. In the event of acute anaphylactic shock, the injection must be stopped immediately and appropriate treatment initiated.

PRESENTATION
300 IU pack: One vial of a sterile, white or pale yellow, dried powder, containing 300 IU factor VIII in a clear glass, evacuated, 30 mL vial fitted with a rubber stopper and aluminium closure. One 10 mL water for injection, a reconstitution set and administration set are provided.
500 IU pack: One vial of a sterile, white or pale yellow, dried powder, containing 500 IU factor VIII in a clear glass, evacuated, 30 mL vial fitted with a rubber stopper and aluminium closure. One 10 mL water for injection, a reconstitution set and administration set are provided.
1000 IU pack: Two vials of a sterile, white or pale yellow, dried powder, each containing 500 IU factor VIII in a clear glass, evacuated, 30 mL vial fitted with a rubber stopper and aluminium closure. Two 10 mL water for injection, a reconstitution set and administration set are provided.

STORAGE DIRECTIONS
Store below 25°C
Protect from light.
Keep out of reach of children.

NAME AND BUSINESS ADDRESS OF APPLICANT
NATAL BIOPRODUCTS INSTITUTE
Company Reg. No. 94/02044/08

PRIVATE BAG X9043	10 EDEN ROAD
PINETOWN	PINETOWN
3600	3610
Telephone : (031) 719 6789	Telefax (031) 708-5614

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
March 1997

P1777 11/98

Approved package insert
Date of approval 06 November 1999

PATIENT INFORMATION LEAFLET FOR

Haemosolvate Factor VIII 300 IU and 500 IU

Information in this monograph is for use as an educational aid only. It does not cover all possible uses, actions, precautions, side effects or interactions of this medicine. Consult your doctor or haemophilia nurse for individualised assistance/advice.

PROPRIETARY NAME:
Haemosolvate^® Factor VIII 300 IU
Haemosolvate^® Factor VIII 500 IU

Please read this patient information leaflet about Haemosolvate Factor VIII carefully before you use this medicine. If any of this information worries you, speak to your doctor, or haemophilia nurse, or contact the nearest Haemophilia Treatment Centre.

SCHEDULING STATUS:
S4

COMPOSITION:
Haemosolvate Factor VIII 300 IU - Each vial of reconstituted solution contains 300 IU (International Units) of human factor VIII concentrate, and >300 IU human factor VIII:vWF (von Willebrand factor).
The solution (per vial) also contains 0,15 g sucrose and less than 0,16 g protein.

Haemosolvate Factor VIII 500 IU - Each vial of reconstituted solution contains 500 IU of human factor VIII concentrate and >500 IU human factor VIII:vWF (von Willebrand factor).
The solution (per vial) also contains 0,15 g sucrose and less than 0,16 g protein.

Haemosolvate Factor VIII is prepared from fresh plasma donated by healthy, unpaid blood donors. To reduce the risk of transmission of infective agents, blood donors and donations are carefully selected. Additionally, the manufacturing method includes a process of solvent detergent treatment, developed to inactivate certain viruses, such as, hepatitis B, hepatitis C and human immunodeficiency virus (HIV).

MEDICINE USES:
Haemosolvate Factor VIII is used to treat or prevent bleeding caused by a deficiency (shortage) of the factor VIII blood clotting factor in the body.
Factor VIII is a protein found in normal human plasma. It is needed to clot the blood and to stop bleeding.
In haemophilia A, there is a shortage of factor VIII clotting factor in the blood. Haemosolvate Factor VIII replaces the missing factor VIII and bleeding is prevented or treated.
Haemosolvate Factor VIII may also be used to prevent or treat bleeding in von Willebrand disease, where there is a shortage of von Willebrand factor.

BEFORE YOU TAKE THIS MEDICINE:
Tell your doctor or haemophilia nurse about all the other medicines you may be taking. This includes prescription medicines and medicines bought without a prescription. This is important because certain medications, for example, aspirin or medicines containing aspirin, should not be used as they affect the clotting process.
Tell your doctor or haemophilia nurse if you have any other medical problems.
It is recommended that you be vaccinated against hepatitis A and B. Please discuss this with your doctor or haemophilia nurse.
Check with your doctor if you are pregnant, intend to become pregnant, or are breastfeeding.
Only use Haemosolvate Factor VIII to correct a confirmed deficiency of factor VIII. Do not use Haemosolvate Factor VIII to correct a deficiency of factor IX (haemophilia B).
If you have had a reaction whilst using Haemosolvate Factor VIII, or suspect that you may be allergic to the product, please discuss this with your doctor or haemophilia nurse.

HOW TO TAKE THIS MEDICINE:
Use Haemosolvate Factor VIII exactly as explained to you. If you are unsure about the use of this product or the dose required, please speak to your doctor or haemophilia nurse.
The dose of Haemosolvate Factor VIII is individualised and depends on your body weight (mass), the severity of your condition, and the nature and site of the bleeding. Your doctor may need to do some blood tests to check your dose, and to see how you are responding to the medicine.
Some patients may, on the advice of the doctor, need to use Haemosolvate Factor VIII together with other medicines.
Haemosolvate Factor VIII is given by slow infusion into a vein.
If a severe allergic reaction occurs, medical attention should be sought immediately. Speak to your doctor or haemophilia nurse about the possible signs of a severe allergic reaction (see “SIDE EFFECTS”).
This medicine has been prescribed for you. Do not share medicines that are prescribed for you with other people.

Recommended dosage guidelines for Haemosolvate Factor VIII:
Before use, dissolve the contents of the Haemosolvate Factor VIII vial in 10 mL Water for Injection (see reconstitution method).
Do not use the product if a gel forms when the water is added.

The dose that you need is calculated to make sure that adequate factor VIII plasma concentrations are reached and maintained. Also, the dose or the length of time that this medicine is used, depends on the effects that it has on you. Based on your response to the medicine, the dose or the length of treatment may need to be changed. Your doctor or haemophilia nurse will advise you on this.
The dose for a child or adult is based on the body weight (mass).

The following formula may be used as a guide to calculate the dose:-
Required Units (IU) =
body mass (kg) x 0,5 x desired factor VIII increase
(% of normal)

Recommended dose to prevent bleeding (prophylaxis):
In order to keep plasma levels of factor VIII at least above 1%, the dose may vary from 10 to 50 IU per kg given into the vein every two to three days.

Recommended dose to treat bleeding:

Mild bleeding episode, e.g. Joint bleeds	Keep plasma level of factor VIII at 30% for at least one day.
Moderate bleeding episode, e.g.Muscle bleeds;Mild injury to the head;Mild bleeds in the mouth	Keep plasma levels of factor VIII at 40-50% for 3-4 days, or until the wound heals.
Severe life threatening bleeding episode, e.g.Severe internal bleeding in the gastro-intestinal tract, in the abdomen or in the head;Fractures	Treatment must be started immediately. The plasma factor VIII level should be raised to 60-100%. Contact your doctor or haemophilia nurse immediately.

To prevent bleeding before and after surgery-
Factor VIII replacement should be started one hour before the procedure.
Other medicines may need to be given together with Haemosolvate Factor VIII.

For a tooth extraction or minor operations	Keep plasma level of factor VIII at 40-50% for 3-4 days or until adequate healing.
For a major operation	High levels of factor VIII are required for extensive periods of time. Your doctor and your haemophilia nurse must be consulted in this regard.

Please speak to your doctor or haemophilia nurse regarding treatment you should take before, during or after surgery.

HOW TO PREPARE HAEMOSOLVATE FACTOR VIII:
Please read all instructions carefully before starting the reconstitution procedure. Only prepare Haemosolvate Factor VIII with the reconstitution set that is provided, because this product must be given in a plastic syringe and must be filtered before it is used.
The Water for Injection in the ampoule has to be added to the powder in the vial in order to dissolve it, so that it can be injected into the body. The procedure below explains how to do this.

The vial and the ampoule containing the Water for Injection should be at room temperature (below 25°C) while reconstituting (mixing) Haemosolvate Factor VIII. If you have been storing the product in the fridge, you will need to warm the product and Water for Injection by holding it in your hand.

Remove the plastic covering cap on the vial.
Wipe the exposed rubber stopper with an antibacterial agent.
Attach the short metal filter needle to the syringe.
Keep the needle attached until just before the solution is infused into the vein.
Break open the diluent ampoule and draw up 10 mL of Water for Injection. See Figure 1.

{Illustrated}
Figure 1
Insert the filter needle, with the syringe attached, through the rubber stopper of the vial. The vacuum present in the vial, will draw the diluent into the vial. Turn the vial gently to wet and dissolve all the powder. See Figure 2. Do not use the product if no vacuum is present. (See “STORAGE AND DISPOSAL”).

Figure 2
In order to minimise foaming, please do not shake the vial. Haemosolvate Factor VIII should not take more than 30 minutes to dissolve. Do not use the product if the solution is turbid (very cloudy appearance), contains particles or if a gel forms after reconstitution.
When all the powder has dissolved, pierce the rubber stopper with the air vent needle to release the vacuum in the vial. Remove the air vent needle.
Repeat the process if more than one vial is needed.
Withdraw the contents of the vial(s) into the syringe. See Figure 3.

Figure 3
Remove the syringe and the filter needle from the vial(s). Invert the syringe, expel any air and then remove the filter needle.
Attach the butterfly needle to the syringe. See Figure 4.

Figure 4
Administer the solution, as a slow intravenous infusion over at least 2 minutes, as soon as possible after reconstitution, but not more than three hours after reconstitution.
Throw away any unused solution. Discard items used to reconstitute and administer Haemosolvate Factor VIII in a responsible manner (see “STORAGE AND DISPOSAL”).

SIDE EFFECTS:
These are possible side effects of the medicine. If they carry on, are severe, or bother you, speak to your doctor, or haemophilia nurse.
Headache, flushing or light-headedness
Nausea
Fever
Itching or skin rash
Swelling of the hands, feet or face
Any difficulty in breathing
Changes in vision
If you notice any other effects, speak to your doctor, or haemophilia nurse.

STORAGE AND DISPOSAL:
Store Haemosolvate Factor VIII in a dark, dry and cool place (below 25°C).
It is recommended that the product is not stored in areas where the temperature is likely to be more than 25°C (for example, in direct sunlight or next to a stove).
If facilities are available, Haemosolvate Factor VIII (product and diluent) may be stored in a fridge (between 2 - 8°C). The product or diluent should not be frozen.
Keep out of the reach of children.
Throw away unused or expired medicines and used syringes or needles in a responsible manner.
In order to decrease the chance of needle-stick injuries, it is recommended that used syringes and needles are discarded by placing them in disposable puncture-resistant containers (e.g. an empty bleach container). Used needles and syringes should not be re-used.

IDENTIFICATION & PRESENTATION:
Each clear, glass vial of Haemosolvate Factor VIII 300 IU contains a sterile, white or pale yellow, dried powder. The vial is fitted with a rubber stopper and an aluminium seal. One 10 mL Water for Injection ampoule, a reconstitution set and a butterfly needle are also supplied.

Each clear, glass vial of Haemosolvate Factor VIII 500 IU contains a sterile, white or pale yellow, dried powder. The vial is fitted with a rubber stopper and an aluminium seal. One 10 mL Water for Injection ampoule, a reconstitution set and a butterfly needle are also supplied.

The 1000 IU pack contains two vials of Haemosolvate Factor VIII 500 IU. The vials contain a sterile, white or pale yellow, dried powder. The vial is fitted with a rubber stopper and an aluminium seal. Two 10 mL Water for Injection ampoules, a reconstitution set and a butterfly needle are also supplied.
Components of the reconstitution set are as follows:
Short metal filter needle
Syringe
Swabs
Air vent needle
Reconstituted solution: The reconstituted solution is a colourless to slightly opalescent solution, which may exhibit slight flocculation. Opalescent solutions exhibit colour changes like an opal.

REGISTRATION NUMBERS:
300 IU: 31/30.3/392
500 IU: Y/30.3/292

NATAL BIOPRODUCTS INSTITUTE
Reg. No. 94/02044/08
Private Bag X9043
PINETOWN
3600
Telephone: (031) 719 6789
Fax: (031) 708 5614

P2093 08/98

Information in this monograph is for use as an educational aid only. It does not cover all possible uses, actions, precautions, side effects or interactions of this medicine. Consult your doctor or haemophilia nurse for further individualised assistance/advice.



Updated on this site: November 1999

Please note that the Natal Bioproducts Institute cannot be held responsible for the accuracy of the text. The package insert on the screen may not be the latest version. We therefore recommend that an alternative source of information be consulted, particularly when confirmation of dosages and indications are required. Please refer to the printed package inserts inside the packs, recognised reference books or alternatively, you may contact the NBI Information Centre at (+27)(+31) 719 6789 or 082 870 3705 or 082 895 0056.
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