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HAEMOSOLVEX FACTOR IX (Powder for Injection)

REGISTRATION NUMBER
W/30.3/191

PROPRIETARY NAME
(and dosage form):

HAEMOSOLVEX FACTOR IX (Powder for Injection)

DESCRIPTIVE NAME OF MEDICINE
Human Factor IX Complex

PHARMACOLOGICAL CLASSIFICATION
A 30.3 Biologicals (Blood Fractions)

SCHEDULING STATUS
S4

COMPOSITION
Factor IX complex (prothrombin complex) is a lyophilised concentrate containing the following coagulation factors: factor II (prothrombin), factor VII (proconvertin), factor IX (Christmas factor) and factor X (Stuart-Prower factor).
Haemosolvex Factor IX is prepared from pooled fresh plasma donated by healthy, non-remunerated 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, hepatitis C and HIV.
When each vial of the product is reconstituted with the 10 mL Water for Injection provided, the solution per vial, will contain factor IX 500 IU (50 IU/mL), factor II >400 IU, factor VII >65 IU and factor X >400 IU.
The preparation has been tested and found negative for the presence of active thrombin. The product is stabilised with 10 IU heparin per mL. The reconstituted solution is isotonic with a sodium content of approximately 300 mmol/L.

IDENTIFICATION
Lyophilised powder: A friable, off-white to light blue powder.
Reconstituted solution: The powder, when reconstituted with Water for Injection, forms a colourless to light blue solution, which may exhibit slight flocculation.

PHARMACOLOGICAL ACTION OF THE MEDICINE
Factor IX is a vitamin K-dependant clotting factor synthesised in the liver. Factor IX is part of the intrinsic pathway of blood coagulation and is required for the pathway’s completion. This pathway results ultimately in the conversion of prothrombin to thrombin and thereby facilitates the formation of a fibrin clot.
Haemosolvex Factor IX complex also contains vitamin K-dependant coagulation factors II, VII and X.
In anti-coagulant haemorrhage (e.g. coumarin drug overdose), the coumarin-derivative anticoagulants act indirectly in the liver by inhibiting the vitamin K-mediated gamma-carboxylation of precursor proteins, thus preventing the usage of these factors in the clotting cascade. The administration of factor IX complex concentrates containing additional vitamin K-dependant clotting factors, increases the plasma concentration of these clotting factors to overcome the effect of the anticoagulant.
Pharmacokinetics:
The plasma half-life of factor IX ranges from 16-30 hours. The plasma half-life of factor II ranges from 40-60 hours, factor VII from 3-6 hours, and factor X from 30-60 hours.

INDICATIONS
Haemosolvex Factor IX may be used for the treatment of coagulation defects caused by either a congenital or an acquired deficiency of factor IX.
Congenital: Haemophilia B.
Acquired: The treatment of severe bleeding resulting from an overdose of oral coumarin-derivative anticoagulants.

CONTRA-INDICATIONS
This preparation is not intended for the treatment of haemophilia A (classical haemophilia) due to factor VIII deficiency.
Do not use the factor IX complex, unless the deficiency has been confirmed.
Factor IX complex is ineffective in bleeding due to heparin.
This product should not be administered to patients with a known allergic reaction to the product, or to those with a high risk of thrombosis or disseminated intravascular coagulation (DIC).
Factor IX complex should not be given in cases of liver damage with evident antithrombin III deficiency as coagulation activation with paradoxical haemorrhage occurs.

DOSAGE AND DIRECTIONS FOR USE
Warnings:
This preparation must be administered as a slow intravenous infusion over at least 2 minutes.
Measures to treat anaphylaxis, including adrenaline and corticosteroids, must be at hand when administering Haemosolvex Factor IX.
If a gel forms on reconstitution, the preparation must not be used.
Do not administer concomitantly with other medicines.
General dosing information:
Dissolve the contents of each vial 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, type of haemorrhage, location of the bleed, type of surgery to be performed and the clinical picture.
Paediatric factor IX dose: Dose is calculated according to the body mass. Refer to the determination of dosage section.
The determination of the factor IX plasma level is useful initially in determining the dose required and thereafter in assuring whether adequate factor IX concentrations have been achieved and are being maintained.
Determination of the dosage:
The calculated required dosage for treatment is based on the empirical finding that 1 IU of factor IX per kg body weight raises the plasma factor IX activity by 0,8% of normal.
The required dosage is determined using the following formula (initial dose):
Required units (IU) = Body weight (kg) x desired factor IX increase (%) x 1,2
The amount to be administered and the frequency of administration should always be oriented towards clinical efficacy and therefore the recommended dosage regimens must be used as a guideline for therapy only. Longer or shorter periods and higher or lower levels of replacement therapy may be necessary.

Treatment guidelines:

Haemorrhagic event (with examples)	Therapeutically necessary plasma level of factor IX activity	Period during which it is necessary to maintain the therapeutic plasma level of factor IX activity
Minor: Spontaneous early bleed; Minor oral bleeds; Nasal haemorrhage; Trauma without the signs of bleeding; Haematuria without pain.	30%	At least one day, depending on the severity of the haemorrhage.
Major: Oral bleeds (including molar tooth extraction and haemorrhage of the throat and tongue); Full symptoms of haemarthrosis; Haemorrhage in the calf or the forearm;	30-50%	3-4 days or until adequate wound healing (see ‘Pharmacokinetics’).
Mild trauma capitis;Severe epistaxis;Retroperitonal bleeding;Trauma with bleeding;Haematuria with pain. Serious injuries;Major operations;Intracranial haemorrhage; Gastro-intestinal haemorrhage.	50% - 75%
Anticoagulant haemorrhage	30%	At least one day, depending on the severity of the haemorrhage.

Note:

•	The potential benefit of treatment with high doses (> 50%) of factor IX complex concentrate should be weighed against the risk of complications resulting from withholding administration.
•	Patients receiving high doses for 4-5 days of treatment should be carefully monitored for potential complications (see SIDE EFFECTS AND SPECIAL PRECAUTIONS).
•	If the patient is not responsive to therapy, consideration should be given to the presence of inhibitors (antibodies to factor IX).

Prevention of bleeding during and following surgical procedures:
Replacement therapy must be initiated one hour prior to the procedure. The factor IX level must be maintained high enough to prevent haemorrhage and promote epithelialisation until healing is complete and sutures are removed (see ‘Treatment guidelines’). Concurrent antifibrinolytic therapy to prevent or decrease bleeding during and following dental surgery may be required (see SIDE EFFECTS AND SPECIAL PRECAUTIONS).

RECONSTITUTION PROCEDURE
Read all instructions before commencing the reconstitution procedure. Use only the injection/infusion set supplied as Haemosolvex Factor IX must be administered via plastic syringes only 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 there is no vacuum present.
5.	Gently swirl the vial until the powder is dissolved. Do not shake and avoid foaming. The reconstitution process should take 30 minutes at the most. Do not use if the 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 the air vent needle.
7.	Withdraw the contents of the vial into the syringe.
8.	Remove the syringe and the filter needle from the vial. Invert the syringe, expel any air, then remove and discard the filter needle.
9.	Attach the BUTTERFLY NEEDLE to the syringe.
10.	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
11.	Discard any unused solution.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Allergic/anaphylactic type reactions, characterised by chills, fever and urticaria, may occur.
In the event of acute anaphylactic shock, the injection must be stopped immediately and appropriate treatment initiated.
Other adverse events such as nausea, vomiting, headache and flushing have been reported particularly following rapid administration. Factor IX complex concentrates have been associated with thrombo-embolic complications, with reports of thrombosis and intravascular coagulation in patients with liver disease. Myocardial infarction has occurred in patients receiving factor IX complex concentrates, and may be associated with high doses.
Infectious diseases due to the transmission of infectious agents cannot be totally excluded. Consideration should be given to appropriate vaccination of patients receiving human blood or plasma-derived medicinal products.
Dental:
Caution should be exercised when administering systemic antifibrinolytics in conjunction with factor IX complex as they may potentiate the thrombogenic effects of factor IX complex concentrates. Using the antifibrinolytic agent as an oral rinse, or delaying its use for 8 to 12 hours after administration of the concentrate, may minimise this complication.
Because of the potential risk of thrombo-embolic complications, caution should be exercised when administering Haemosolvex Factor IX to patients with a history of coronary heart disease or myocardial infarction, to patients with liver disease, to patients post-operatively, to neonates, or to patients at risk of thrombo-embolic episodes.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF TREATMENT
The use of high doses or prolonged continuous usage of factor IX complex concentrates, has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism, due to accumulation of factors II and X. Therefore, in cases of overdosage, the development of thrombo-embolic complications or disseminated intravascular coagulation is enhanced in patients at risk of these complications.
Appropriate measures for the treatment of thrombo-embolic complications or disseminated intravascular coagulation should be initiated, should these occur.

PRESENTATION
500 IU: One vial of a sterile, off-white to light blue dried powder, containing 500 IU factor IX complex in a clear glass, evacuated, 30 mL vial fitted with a rubber stopper and an aluminium closure. One 10 mL Water for Injection ampoule, a reconstitution set and an administration set are also provided.

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

NAME AND BUSINESS ADDRESS OF THE APPLICANT
NATAL BIOPRODUCTS INSTITUTE
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 PACKAGE INSERT
01/91

P1284 11/98

PATIENT INFORMATION LEAFLET FOR

HAEMOSOLVEX FACTOR IX (Powder for injection)

Please read this patient information leaflet about Haemosolvex Factor IX 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:
Haemosolvex Factor IX - each vial of reconstituted solution contains the following blood clotting factors:
Factor IX (Christmas factor)        500 IU (50 IU/mL)
Each vial also contains clotting factors II, VII and X.
The solution (per vial) contains 10 IU heparin/mL and sodium 300 mmol/L.

Haemosolvex Factor IX is prepared from fresh plasma donated by healthy, unpaid donors. To reduce the risk of transmission of infective agents, blood donors and donations are carefully selected. In addition, 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:
Haemosolvex Factor IX is used to treat blood-clotting problems caused by a deficiency (shortage) of the factor IX blood clotting factor in the body. A shortage of factor IX can be caused by haemophilia B or can be from an overdose of medicines that thin the blood, for example, warfarin.
Factor IX is a protein found in normal human plasma. It is needed to clot the blood and stop the bleeding.
In haemophilia B, there is a shortage of this factor IX blood clotting factor. Haemosolvex Factor IX replaces the missing factor IX so that a clot will form and stop the bleeding.

BEFORE YOU TAKE THIS MEDICINE:
Tell your doctor or haemophilia nurse about all the other medicines that 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 if you have any other medical problems, such as, liver problems, a history of thrombosis or any other problems with blood clotting, heart disease or a history of heart attack.
Check with your doctor if you are pregnant, intend to become pregnant or are breastfeeding.
Do not mix Haemosolvex Factor IX together with any other medicines in the injection syringe.
Only use Haemosolvex Factor IX to correct a verified deficiency of factor IX. Do not use Haemosolvex Factor IX to correct a deficiency of factor VIII (Haemophilia A).
If you have had a reaction whilst using Haemosolvex Factor IX, 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 Haemosolvex Factor IX exactly as explained to you. If you are unsure about the use of this product or the dose that is required, please speak to your doctor or haemophilia nurse.
The dose of Haemosolvex Factor IX is individualised and depends on your body weight, the severity of your condition and the nature and site of the bleeding. Your doctor may, at first, need to do some blood tests to determine the dose you need and, later, to see how you are responding to the medicine.
Haemosolvex Factor IX 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.

Usual recommended dose of Haemosolvex Factor IX:
Before use, dissolve the contents of the Haemosolvex Factor IX 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 IX 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 desired factor IX increase (%) x 1,2

The dose of Haemosolvex Factor IX and how often it should be taken, is based on the effect that the product has on the body. The following dosing regimens are only a guideline as longer or shorter periods and higher or lower doses may be preferred in some patients.

Bleeding event	Target plasma level of factor IX activity	Duration of therapy
Minor Nose bleeds Minor mouth bleeds Trauma with no signs of bleeding Blood in the urine (but no pain)	30%	At least one day depending on the severity of the bleeding event

Bleeding event	Target plasma level of factor IX activity	Duration of therapy
Major Oral bleeds such as from molar tooth extractions and severe bleeding of the throat and tongue Bleeding in the calf or forearm.	30-50%	3 to 4 days or until the wound has healed well
Head trauma or any bleeding in or from the head Severe nose bleeds Any internal bleeding Major operations Trauma with bleeding or any serious injuries Blood in the urine with pain	50-75%

For severe bleeds, please contact your doctor or haemophilia nurse immediately.

NOTE:
Patients using high doses of factor IX complex for more than 4-5 days should be on the watch for any possible problems from the medicine (See section on SIDE EFFECTS.)
If you do not have the usual response, or have no response to therapy, speak to your doctor or haemophilia nurse.

Prevention of bleeding during and after surgery
Please speak with your doctor or haemophilia nurse if you are aware that you will be undergoing any surgery/surgical procedures. They will need to advise you on how best to handle your individual situation.
Treatment with Haemosolvex Factor IX should be started at least one hour before surgery.
The dose of Haemosolvex Factor IX must prevent excess bleeding and promote wound healing until the stitches are removed.
Medicines to stop or reduce bleeding during and after dental surgery may be needed. Your doctor may advise you to use such a medicine as a mouth rinse, or to wait for 8 to 12 hours after taking Haemosolvex Factor IX before taking such a medicine.

HOW TO PREPARE HAEMOSOLVEX FACTOR IX:
Only prepare Haemosolvex Factor IX with the injection set that is provided as this product must be given in a plastic syringe and must be filtered before it is used.
The vial and the ampoule containing the Water for Injection should be at room temperature (below 25°C) while reconstituting (mixing) Haemosolvex Factor IX. 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 one of the alcohol swabs provided.
Attach the short metal filter needle to the syringe. Keep the needle attached until just before the medicine 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. A vacuum 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 the foaming, please do not shake the vial. Haemosolvex Factor IX should not take longer 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 and then throw away 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. Throw the filter needle away.
Attach the butterfly needle to the syringe. See Figure 4.

Figure 4
After cleaning the site to be injected with the second alcohol swab, inject the solution, as a slow intravenous infusion over at least 2 minutes. The reconstituted solution should be administered as soon as possible, but not more than 3 hours after reconstitution.
Throw away any unused solution. Discard the items used to reconstitute and administer Haemosolvex Factor IX in a responsible manner (see "STORAGE AND DISPOSAL").

SIDE EFFECTS:
Headache or flushing
Nausea or vomiting
These possible side effects are usually related to the rate of infusion of the medicine. You are less likely to have side effects if you infuse the solution slowly. However, if these carry on, are severe, or bother you, speak to your doctor or haemophilia nurse.
Speak to your doctor or haemophilia nurse at once if you notice:-
Allergic reactions such as fever and chills, or skin rash
Any difficulty in breathing or chest pain
Any unusual bleeding or pain
If you notice any other effects, speak to your doctor or haemophilia nurse.

STORAGE AND DISPOSAL:
Store Haemosolvex Factor IX in a dark 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, Haemosolvex Factor IX (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 number of needle stick injuries, it is recommended that used syringes and needles are discarded by placing them in disposable puncture resistant containers (e.g. empty bleach container). Used needles and syringes should not be re-used.

IDENTIFICATION & PRESENTATION:
Each clear glass vial of Haemosolvex Factor IX 500 IU contains a sterile, off-white to light blue 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 reconstituted solution forms a colourless to light blue solution that may contain a few visible floccules (fine hair-like structures).

Components of the reconstitution set are as follows:
Short metal filter needle
Syringe
Alcohol swab
Air vent needle

OVERDOSE:
If you think you have used too much of Haemosolvex Factor IX, contact your doctor or haemophilia nurse at once.

REGISTRATION NUMBERS:
500 IU: W/30.3/191

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

P number: P3004 03/99

Information in this monograph is for use as an educational aid only. It is not intended as individual advice. It does not cover all possible uses, actions, precautions, side effects or interactions of this medicine. Consult your doctor, pharmacist or health care worker for further individualised 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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