BeneFIX 2000 IU powder and solvent for solution forinjection

BeneFIX is a coagulation factor IX product that is produced by recombinant technology. Patients with haemophilia B (Christmas disease) are deficient in coagulation factor IX. BeneFIX works by replacing factor IX in haemophilia B patients to enable their blood to clot.

BeneFIX is used for the treatment and prevention of bleeding (prophylaxis) in patients with haemophilia B (congenital factor IX deficiency).

Do not take BeneFIX

• If you are allergic (hypersensitive) to nonacog alfa or any of the other ingredients of BeneFIX.
• If you are allergic (hypersensitive) to hamster proteins.

Take special care with BeneFIX

• See your doctor immediately if your bleeding does not stop as expected.
• Activity-neutralizing antibodies (inhibitors) are an uncommon event in previously treated patients (PTPs) receiving factor IX-containing products. Since during clinical studies one PTP treated with BeneFIX developed a clinically relevant low responding inhibitor, and experience on antigenicity with recombinant factor IX is still limited, while being treated with BeneFIX you should be

carefully monitored for the development of factor IX inhibitors. Sufficient data have not been obtained from ongoing clinical studies on the treatment of previously untreated patients (PUPs), with BeneFIX.

• Clinical studies on BeneFIX did not determine whether patients aged 65 and over respond differently from younger subjects. As for any patient receiving BeneFIX, if you are elderly your doctor will choose a specific dose appropriate for you.
• As with any intravenous protein product, allergic type hypersensitivity reactions are possible. The product may contain traces of hamster proteins. Potentially life-threatening anaphylactic reactions have occurred with factor IX products, including BeneFIX. You will be informed of early signs of hypersensitivity reactions including difficulty breathing, shortness of breath, swelling, hives, itching, tightness of the chest, wheezing, low blood pressure, blurred vision and anaphylaxis (severe allergic reaction that can cause difficulty in swallowing and/or breathing, red or swollen face and/or hands).
• If allergic or anaphylactic-type reactions occur, stop the infusion immediately and contact a doctor or seek emergency medical care immediately. In case of severe allergic reactions, alternative therapy should be considered.
• There have been reports in the literature showing a correlation between the occurrence of a factor IX inhibitor and allergic reactions. Therefore, if you experience allergic reactions such as difficulty breathing, shortness of breath, swelling, hives, itching, tightness of the chest, wheezing, hypotension, or blurred vision, you should be evaluated for the presence of an inhibitor. It should be noted that patients with factor IX inhibitor may be at an increased risk of anaphylaxis with subsequent challenge with factor IX.
• The production of factor IX in the body is controlled by the factor IX gene. Patients who have major deletion mutations of their factor IX gene may be more likely to have factor IX inhibitor and an allergic reaction. Therefore if you are known to have a major deletion mutation of the factor IX gene, your doctor will monitor you more closely for signs of an allergic reaction particularly when you first start to take BeneFIX.
• Because of the risk of allergic reactions with factor IX concentrates, your initial administrations of factor IX should, according to the treating physician?s judgement, be performed under medical observation where proper medical care for allergic reactions can be provided.
• Even in the absence of factor IX inhibitor, higher doses of BeneFIX may be needed than required for plasma-derived factor IX. Therefore, close monitoring of factor IX plasma activity and pharmacokinetic assessment have to be performed in order to adjust doses as appropriate. If bleeding is not controlled with the recommended dose, contact your doctor.
• If you suffer from a liver or cardiac disease or if you have recently had surgery, there is an increased risk for coagulation complications.
• There have been reports of agglutination of red blood cells in the tube/syringe with the administration of BeneFIX. So far, no clinical sequelae have been reported in association with this observation. To minimize the possibility of agglutination, it is important to limit the amount of blood entering the tubing. Blood should not enter the syringe. If agglutination of red blood cells in the tubing/syringe is observed, discard all this material (tubing, syringe and BeneFIX solution) and resume administration with a new package.
• A kidney disorder (nephrotic syndrome) has been reported following high doses of plasma-derived Factor IX to induce immune tolerance in haemophilia B patients with factor IX inhibitors and a history of allergic reactions.
• It is recommended that, whenever possible, every time you use BeneFIX, the name and batch number of the product is registered.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding you should only take BeneFIX upon specific instructions from your physician. It is not known whether BeneFIX can affect reproductive capacity or cause foetal harm when given to pregnant women. Your doctor may advise you to stop treatment with BeneFIX if you are breast-feeding or become pregnant.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

No studies on the effects on the ability to drive and use machines have been performed.

Always take BeneFIX exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are not sure.

Your doctor will decide the dose of BeneFIX you will receive. This dose and duration will depend upon your individual needs for replacement factor IX therapy and upon pharmacokinetics (recovery and half-life) that have to be checked regularly. You may notice a difference in the dose you receive if you are changing from a plasma-derived factor IX product to BeneFIX.

Your doctor may decide to change the dose of BeneFIX you receive during your treatment.

Reconstitution and administration

The procedures below are provided as guidelines for the reconstitution and administration of BeneFIX. Patients should follow the specific venipuncture procedures provided by their physicians.

BeneFIX is administered by intravenous (IV) injection after reconstitution of the powder for injection with the supplied solvent (0.234% w/v sodium chloride solution) in the pre-filled syringe.

Always wash your hands prior to performing the following procedures. Aseptic technique (meaning clean and germ free) should be used during the reconstitution procedure.

Reconstitution:

BeneFIX will be administered by intravenous infusion (IV) after reconstitution with sterile solvent for injection.

1. Allow the vial of lyophilised BeneFIX and the pre-filled syringe to reach room temperature.

2. Remove the plastic flip-top cap from the BeneFIX vial to expose the central portion of the rubber stopper.

3. Wipe the top of the vial with an alcohol swab provided, or use another antiseptic solution and allow to dry. After cleaning do not touch the rubber stopper with your hand or allow it to touch any surface.

4. Peel back the lid from the clear plastic vial adapter package. Do not remove the adapter from the package.

5. Place the vial on a flat surface. While holding the adapter in the package, place the vial adapter over the vial. Press down firmly on the package until the adapter snaps into place on top of the vial, with the adapter spike penetrating the vial stopper.

6. Lift the package away from the adapter and discard the package.

7. Attach the plunger rod to the solvent syringe by pushing and turning firmly.

8. Break off the tamper-resistant plastic tip cap from the solvent syringe by snapping the perforation of the cap. This is done by bending the cap up and down until the perforation is broken. Do not touch the inside of the cap or the syringe tip. The cap may need to be replaced (if not administering reconstituted BeneFIX immediately), so set it aside by placing it on its top.

9. Place the vial on a flat surface. Connect the solvent syringe to the vial adapter by inserting the tip of the syringe into the adapter opening while firmly pushing and turning the syringe clockwise until the connection is secured.

10. Slowly depress the plunger rod to inject all the solvent into the BeneFIX vial

11. With the syringe still connected to the adapter, gently rotate the vial until the powder is dissolved.

12. The final solution should be inspected visually for particulate matter before administration. The solution should appear clear and colourless.

Note: If you use more than one vial of BeneFIX per infusion, each vial should be reconstituted as per the previous instructions. The solvent syringe should be removed, leaving the vial adapter in place, and a separate large luer lock syringe may be used to draw back the reconstituted contents of each individual vial.

13. Ensuring that the syringe plunger rod is still fully depressed, invert the vial. Slowly draw back all the solution into the syringe.

14. Detach the syringe from the vial adapter by gently pulling and turning the syringe counter-clockwise. Discard the vial with the adapter attached.

Note: If the solution is not to be used immediately, the syringe cap should be carefully replaced. Do not touch the syringe tip or the inside of the cap.

BeneFIX should be administered immediately or within 3 hours after reconstitution. The reconstituted solution may be stored at room temperature prior to administration.

Administration (Intravenous Injection):

BeneFIX should be administered using the pre-filled solvent syringe provided or a single sterile disposable plastic luer lock syringe. In addition, the solution should be withdrawn from the vial using the vial adapter.

BeneFIX should be injected intravenously over several minutes. Your doctor may change your recommended infusion rate to make the infusion more comfortable.

Because the use of BeneFIX by continuous infusion (drip) has not been evaluated, BeneFIX should not be mixed with infusion solutions or be given in a drip.

Please dispose of all unused solution, empty vials and used needles and syringes in an appropriate container for throwing away waste as it may hurt others if not handled properly.

If you take more BeneFIX than you should

Please contact your doctor immediately if you inject more BeneFIX than your doctor recommends.

If you stop taking BeneFIX

If you have any further questions on the use of this product, ask your physician or pharmacist.

Like all medicines, BeneFIX can cause side effects, although not everybody gets them.

Should you experience a significant increase in your usage of BeneFIX in order to control a bleed, please contact your doctor immediately; your blood should be checked for inhibitors to factor IX activity.

Possible side effects are listed according to the following categories:
Uncommon: between 1 in 100 and 1 in 1,000 patients
Rare: between 1 in 1,000 and 1 in 10,000 patients

Immune system disorders

Uncommon Rare Development of neutralising antibodies inhibitors Hypersensitivityallergic reactions such reactions may include burning sensation in jaw and skull, chills rigors, dry coughsneeze, flushing, lethargy, restlessness, tingling, hives, itching and rash, low blood pressure, fast heart rate, tightness of the chest, wheezing, swelling of the throat, anaphylaxis, rash, blurred vision

Nervous system disorders

Uncommon Dizziness, headache, altered taste, lightheadedness

Gastrointestinal disorders

Uncommon Rare Nausea Vomiting

General disorders and administration site conditions

Uncommon discomfort Rare Injection site reactions including burning and stinging at the infusion site, at the IV site, cellulites, phlebitis Fever

* See additional information below.

Hypersensitivity/allergic reactions

Hypersensitivity or allergic reactions have been infrequently observed in patients treated with factor IX containing products, including BeneFIX. In some cases, these reactions have progressed to severe anaphylaxis. Allergic reactions have occurred in close temporal association with development of factor IX inhibitor (see also ?Take special care with BeneFIX?).

The aetiology of the allergic reactions to BeneFIX has not yet been elucidated. These reactions are potentially life-threatening. If allergic/anaphylactic reactions occur, stop the infusion immediately and contact your doctor or seek emergency medical care immediately. In case of severe allergic reactions, alternative therapy should be considered. The treatment required depends on the nature and severity of side-effects (see also ?Take special care with BeneFIX?).

Inhibitor development

Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. 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.

A clinically relevant, low responding inhibitor was detected in 1 out of 65 BeneFIX patients who had previously received plasma-derived products. This patient was able to continue treatment with BeneFIX with no rise in inhibitor or anaphylaxis. Patients treated with BeneFIX should be monitored for inhibitor development.

There are insufficient data to provide information on inhibitor incidence in previously untreated patients (PUPs).

Due to the production process BeneFIX may contain trace amounts of hamster cell proteins. Hypersensitivity responses can occur.

A kidney disorder has been reported following high doses of plasma-derived Factor IX to induce immune tolerance in haemophilia B patients with factor IX inhibitors and a history of allergic reactions (see also ?Take special care with BeneFIX?).

Renal

One patient developed severe abdominal pain which was caused by an area of the kidney that lacked the necessary blood supply (referred to as a renal infarct). The relationship of the infarct to prior administration of BeneFIX is uncertain.

Thrombotic events

BeneFIX may increase the risk of thrombosis (abnormal blood clots) in your body if you have risk factors for developing blood clots, including an indwelling venous catheter, through which BeneFIX is given by continuous infusion. There have been reports of severe blood clotting events, including life-threatening blood clots in critically ill neonates, while receiving continuous-infusion BeneFIX through a central venous catheter. Cases of peripheral thrombophlebitis and deep venous thrombosis have also been reported; in most of these cases, BeneFIX was administered via continuous infusion, which is not an approved method of administration.

Inadequate therapeutic response and inadequate factor IX recovery

Inadequate therapeutic response and inadequate factor IX recovery have been reported during the post-marketing use of BeneFIX.

If any of the side effects get serious, or if you notice any side effect not listed in this leaflet, please tell your doctor or pharmacist.

Keep out of the reach and sight of children.

Do not use after the expiry date stated on the outer box and vial label. The expiry date refers to the last day of that month.

Do not use BeneFIX if the solution is not clear or colourless.

BeneFIX must be stored continuously in a refrigerator at a temperature of 2°C to 8°C and must be used by the expiry date on the label. For the purpose of ambulatory use the product may be removed from such storage for one single period of maximum 6 months at room temperature (up to 30°C).At the end of this period the product should not be put back in the refrigerator, but should be used or discarded. The date the product is removed from the refrigerator and set at room temperature (not exceeding 30 oC) and the date the vial should be withdrawn should be noted on the outer carton.

Do not freeze in order to prevent damage to the pre-filled syringe.

Use the reconstituted solution immediately or within 3 hours.

Use only the pre-filled syringe provided in the box for reconstitution. Other sterile disposable syringes may be used for administration.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

What BeneFIX contains

• The active substance is nonacog alfa (recombinant coagulation factor IX). Each vial of BeneFIX contains nominally 250, 500, 1000 or 2000 IU of nonacog alfa.
• The other ingredients are sucrose, glycine, L-histidine, polysorbate 80. A solvent (0.234% sodium chloride solution) is also supplied for reconstitution.
• After reconstitution with the supplied solvent (0.234% sodium chloride solution), each vial contains 50, 100, 200 or 400 IU/ml (see Table 1).

Table 1. Strength of BeneFIX per ml prepared solution

Amount of BeneFIX per Vial Amount of BeneFIX per 1 ml of prepared solution for injection 250 IU 50 IU 500 IU 100 IU 1000 IU 200 IU 2000 IU 400 IU

What BeneFIX looks like and contents of the pack

BeneFIX is provided as a powder for injection in a glass vial and a solvent provided in pre-filled syringe.

The contents of the pack are:

one vial of BeneFIX 250, 500 1000 or 2000 IU powder one pre-filled syringe of solvent, 5 ml sterile 0.234 sodium chloride solution for injection for reconstitution, with one plunger rod one sterile vial adapter reconstitution device one sterile infusion set two alcohol swabs one plaster one gauze pad

Marketing Authorisation Holder

Wyeth Europa Ltd.
Huntercombe Lane South
Taplow, Maidenhead
Berkshire, SL6 0PH
United Kingdom

Manufacturer

Wyeth Farma S.A.
Autovia del Norte. A-1, Km. 23. Desvio Algete, Km. 1, 28700 S. Sebastian de los Reyes, Madrid Spain

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

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