Consumer medicine information

BeneFIX

Nonacog alfa

BRAND INFORMATION

Brand name

BeneFIX

Active ingredient

Nonacog alfa

Schedule

Unscheduled

SUMMARY CMI

BeneFIX^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using BeneFIX?

BeneFIX contains the active ingredient nonacog alfa, a coagulation factor IX product. BeneFIX is used to control and treat bleeding and prevent bleeding in people with haemophilia B. People with haemophilia B are deficient in coagulation factor IX.

For more information, see Section 1. Why am I using BeneFIX? in the full CMI.

2. What should I know before I use BeneFIX?

Do not use BeneFIX if you have had an allergic reaction to nonacog alfa, hamster proteins or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use BeneFIX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with BeneFIX and affect how it works. For more information, see Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use BeneFIX?

BeneFIX comes in five dosage strengths. Your doctor will prescribe the dosage strength and dose that is right for you.
BeneFIX is given by injection directly into your veins.
The BeneFIX powder needs to be reconstituted (made-up) before use. Use only the materials provided in the pack for dissolving the BeneFIX powder with the sodium chloride solution and injecting the made-up BeneFIX solution.
Your doctor, nurse or pharmacist will show you how to use BeneFIX before you use it for the first time.

More instructions can be found in Section 4. How do I use BeneFIX? in the full CMI.

5. What should I know while using BeneFIX?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using BeneFIX. See your doctor immediately if your bleeding does not stop as expected. Stop the infusion immediately and contact your doctor if you experience an allergic reaction.
Things you should not do	Do not stop using this medicine or lower the dose without first checking with your doctor, unless you have an allergic reaction.
Driving or using machines	BeneFIX is not expected to affect your ability to drive or operate machinery.
Looking after your medicine	Store BeneFIX in the refrigerator (2°C to 8°C). Do not freeze. BeneFIX may be stored at room temperature (below 30°C) for a single period up to 6 months. If stored at room temperature it cannot be returned to the refrigerator and must be used within 6 months. Use the made-up solution of BeneFIX as soon as possible or within 3 hours after reconstitution.

For more information, see Section 5. What should I know while using BeneFIX? in the full CMI.

6. Are there any side effects?

General and administration site side effects have been reported, and are usually mild and temporary. Allergic reactions have been reported for all factor IX products, including BeneFIX. Signs of allergic reactions include a skin rash, itching, chest tightness, wheezing, dizziness, hives, faintness, rapid heartbeat, blurred vision, shortness of breath and/or a swollen face.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

BeneFIX^®

Active ingredient(s): nonacog alfa (recombinant coagulation factor IX)

Consumer Medicine Information (CMI)

This leaflet provides important information about using BeneFIX. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using BeneFIX.

Where to find information in this leaflet:

1. Why am I using BeneFIX?
2. What should I know before I use BeneFIX?
3. What if I am taking other medicines?
4. How do I use BeneFIX?
5. What should I know while using BeneFIX?
6. Are there any side effects?
7. Product details

1. Why am I using BeneFIX?

BeneFIX contains the active ingredient nonacog alfa. Nonacog alfa is a coagulation factor IX product that is produced by recombinant technology. Mammalian cells, which have the DNA for human coagulation factor IX put in them, are grown in large amounts in cell culture laboratories. These cells make recombinant human factor IX, which is released into cell culture media and then very highly purified. The recombinant factor IX does not contain any human blood, preservatives, or added animal or human components.

People with haemophilia B (Christmas disease) are deficient in coagulation factor IX. BeneFIX works by replacing factor IX to enable blood to clot.

BeneFIX is used to control and treat bleeding and to prevent bleeding in people with haemophilia B.

2. What should I know before I use BeneFIX?

Warnings

Do not use BeneFIX if:

you are allergic to hamster proteins or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

Signs of allergy include a skin rash, itching, chest tightness, wheezing, dizziness, hives, faintness, rapid heartbeat, blurred vision, shortness of breath and/or a swollen face. If any of these signs occur, stop using BeneFIX and see your doctor immediately, you may need urgent medical care.

Check with your doctor if you:

have liver disease
are at risk of developing clotting disorders other than haemophilia
have recently had surgery.

These conditions increase your risk for clotting complications.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. It is not known whether BeneFIX can affect your ability to have children or harm your developing baby.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known whether BeneFIX passes into breastmilk.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with BeneFIX and affect how well it works.

You may need to use different amounts of your medicine or you may need to take different medicines. Your doctor will advise you.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect BeneFIX.

4. How do I use BeneFIX?

How much to use

BeneFIX comes in five dosage strengths. Your doctor will prescribe the dosage strength and dose that is right for you. The dose and duration will depend on your individual needs for replacement factor IX therapy. If you have been using plasma-derived factor IX, the dose of BeneFIX may differ from the dose of plasma-derived factor IX.
Your doctor may decide to change the dose of BeneFIX during your treatment.
Follow the instructions provided and use BeneFIX until your doctor tells you to stop.

How to use BeneFIX

BeneFIX is given as an injection directly into your veins, usually by yourself, a doctor, nurse, or other trained person.
BeneFIX contains no additives that would prevent the growth of bacteria once the powder is dissolved with sterile sodium chloride solution. For this reason, each vial of BeneFIX is for single use only, in one patient only. Discard any residue.
Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.
When injecting BeneFIX you must follow the detailed instructions provided in the leaflet in the pack.
If you do not understand the instructions for injecting BeneFIX found in the pack, ask your doctor or pharmacist for help.
When you have finished injecting BeneFIX, discard the needle and syringe into a sharps container.

How to reconstitute and administer BeneFIX

Always wash your hands before doing the following procedures. Use germ-free methods during the make-up (reconsitution) procedure and during injection.
Use only the materials provided in the pack for dissolving the BeneFIX powder with the sodium chloride solution and then injecting the made-up BeneFIX solution.
Inject BeneFIX solution as soon as possible or within 3 hours after dissolving the powder.
The made-up solution may be stored at room temperature before injection.
Inject the BeneFIX solution intravenously over several minutes. The rate if injection should be determined by your comfort level.
If you see clumping of red blood cells in the tubing or syringe, discard all this material (tubing, syringe and BeneFIX solution) and start again with a new package.

Clumping together of red blood cells in the tubing or syringe has been noticed when BeneFIX is given to patients. No side effects have been reported when this clumping has occurred. To minimise the risk of clumping, it is important to limit the amount of blood entering the tubing. Blood should not enter the syringe.

If you forget to use BeneFIX

BeneFIX should be used regularly as agreed with your doctor. If you miss your dose at the usual time, you should inject the next dose as soon as you remember.

If it is almost time for your next dose, skip the dose you missed and inject your next dose when you are meant to.

Do not inject a double dose to make up for the dose you missed.

If you use too much BeneFIX

If you think that you have used too much BeneFIX, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using BeneFIX?

Things you should do

See your doctor immediately if your bleeding does not stop as expected.

Stop the infusion immediately if you experience an allergic reaction such as skin rash, itching, chest tightness, wheezing, dizziness, hives, faintness, chills, flushing, rapid heartbeat, shortness of breath and/or a swollen face.

Call your doctor straight away if you:

are using increasing amounts of BeneFIX in order to control a bleed
experience an allergic reaction.

Remind any doctor, dentist or pharmacist you visit that you are using BeneFIX.

During your treatment with BeneFIX, your blood will be checked for inhibitors to factor IX activity. Inhibitors are antibodies against factor IX, which are made by your immune system. The inhibitors stop the factor IX from working as well as it used to.

Things you should not do

Do not stop using this medicine or lower the dosage without first checking with your doctor, unless you have an allergic reaction.
Do not give BeneFIX to anyone else, even if they have the same condition as you.
Do not use BeneFIX to treat any other complaints unless your doctor tells you to.

Driving or using machines

BeneFIX is not expected to affect your ability to drive or operate machinery.

Looking after your medicine

Follow the instructions on the carton on how to take care of your medicine properly.

Keep BeneFIX in the refrigerator (2°C to 8°C). Do not freeze.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

BeneFIX may be stored at room temperature (below 30°C) for a single period up to 6 months. If BeneFIX is stored at room temperature it may not be retuned to refrigerated storage and must be used within 6 months. Write the date on the package when you first store BeneFIX at room temperature.

Do not use this medicine after the expiry date.

Keep BeneFIX (and needles) where young children cannot reach it.

After reconstitution

To stop bacterial contamination of the solution, use the made-up BeneFIX solution as soon as possible or within 3 hours after reconstitution.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Dispose of all unused sodium chloride solution, empty vials, used syringes and needles into a sharps container.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, they are mostly minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Side effects

Side effects	What to do
headache runny or blocked nose or sneezing light-headedness fever chills flushing nausea vomiting diarrhoea feeling of tiredness, drowsiness, or lack of energy discomfort or swelling at the injection site altered taste coughing burning sensation in the jaw or skull changes in your vision tremor	Speak to your doctor if you have any of these side effects and they worry you. These are all mild side effects of BeneFIX injection and will usually disappear on their own. Tell your doctor if they continue.

Serious side effects

Serious side effects	What to do
Allergic reaction: skin rash itching chest tightness wheezing dizziness hives faintness rapid heartbeat shortness of breath a swollen face blurred vision	Stop using BeneFIX and call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people. Tell your doctor if you notice anything else that is making you feel unwell.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop treatment with any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What BeneFIX contains

Active ingredient (main ingredient)	nonacog alfa
Other ingredients (inactive ingredients)	glycine, sucrose, histidine, polysorbate 80, sodium chloride solution (0.234%)

Do not use this medicine if you are allergic to any of these ingredients or hamster proteins.

What BeneFIX looks like

BeneFIX comes as a white powder in a glass vial.

Each vial of BeneFIX is provided with a pre-filled diluent syringe containing 0.234% sodium chloride solution and accessories required for making up the solution and injection. These include a plunger rod, a sterile infusion set, a sterile vial adapter, sticking plaster, a sterile gauze pad and two (2) alcohol swabs.

BeneFIX 250 IU: AUST R 128339

BeneFIX 500 IU: AUST R 128375

BeneFIX 1000 IU: AUST R 128377

BeneFIX 2000 IU: AUST R 128378

BeneFIX 3000 IU: AUST R 203316

Who distributes BeneFIX

BeneFIX is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizermedinfo.com.au

BeneFIX is supplied in New Zealand by:

Pfizer New Zealand Limited
PO Box 3998
Auckland
Toll Free Number: 0800 736 363
www.pfizermedinfo.co.nz

The BeneFIX administration kit is prepared by Wyeth Farma, Algete, San Sebastian de los Reyes, Madrid, Spain.

This leaflet was prepared in November 2021.

® Registered trademark

Published by MIMS January 2022

BRAND INFORMATION

Brand name

BeneFIX

Active ingredient

Nonacog alfa

Schedule

Unscheduled

1 Name of Medicine

Nonacog alfa.

2 Qualitative and Quantitative Composition

The potency (in international units, IU) is determined using an in vitro one stage clotting assay against the World Health Organization (WHO) International Standard for Factor IX concentrate. One IU is the amount of factor IX activity present in 1 mL of pooled, normal human plasma. The specific activity of BeneFIX is greater than or equal to 200 IU per milligram of protein. BeneFIX is not derived from human blood and contains no preservatives or added animal or human components. BeneFIX is inherently free from the risk of transmission of human blood borne pathogens such as HIV, hepatitis viruses and parvovirus.
BeneFIX is formulated as a sterile, non-pyrogenic, lyophilised powder preparation. BeneFIX is intended for intravenous (IV) injection. It is available in single use vials containing the labelled amount of factor IX activity, expressed in IU. Each vial contains nominally 250, 500, 1000, 2000 or 3000 IU of nonacog alfa.
For full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sterile, lyophilised white powder for injection.
All dosage strengths yield a clear, colourless solution upon reconstitution.

4 Clinical Particulars

4.1 Therapeutic Indications

BeneFIX is indicated for the control and prevention of haemorrhagic episodes in patients with haemophilia B (congenital factor IX deficiency or Christmas disease), including control and prevention of bleeding in surgical settings.
BeneFIX is not indicated for the treatment of other factor deficiencies (e.g. factors II, VII and X), nor for the treatment of haemophilia A patients with inhibitors to factor VIII, nor for the reversal of coumarin induced anticoagulation, nor for the treatment of bleeding due to low levels of liver dependent coagulation factors.

4.2 Dose and Method of Administration

Dosage for treatment.

Treatment with BeneFIX should be initiated under the supervision of a physician experienced in the treatment of haemophilia B. BeneFIX is for single use in one patient only.
If any suspected hypersensitivity reaction takes place that is thought to be related to the administration of BeneFIX, the rate of infusion should be decreased or the infusion stopped (see Section 4.4 Special Warnings and Precautions for Use).
Treatment with all factor IX products, including BeneFIX, requires individualised dosage adjustment. The dosage and duration of treatment for all factor IX products depend on the severity of the factor IX deficiency, the location and extent of bleeding and the patient's clinical condition, age and recovery of factor IX.
Dosing of BeneFIX may differ from that of plasma derived factor IX products. To ensure that the desired factor IX activity level has been achieved, precise monitoring using the factor IX activity assay is advised, in particular for surgical interventions. In order to adjust the dose as appropriate, doses should be titrated taking into consideration factor IX activity, pharmacokinetic parameters, such as half-life and recovery, as well as the clinical situation (see Section 4.4 Special Warnings and Precautions for Use).
In an eleven patient crossover randomised pharmacokinetic evaluation of BeneFIX and a single lot of high purity plasma derived factor IX, the recovery was lower for BeneFIX (see Section 5.2 Pharmacokinetic Properties).
In the clinical efficacy studies, patients were initially administered the same dose previously used for plasma derived factor IX. Even in the absence of factor IX inhibitors, approximately half of the patients increased their dose in these studies.
Titrate the initial dose upward if necessary to achieve the desired clinical response. As with some plasma derived factor IX products, patients at the low end of the observed factor IX recovery may require upward dosage adjustment to as much as two times (2 x) the initial empirically calculated dose in order to achieve the intended rise in circulating factor IX activity. The amount of BeneFIX to be infused, as well as the frequency of infusion, will vary with each patient and clinical situation.
BeneFIX may also be administered on a regular schedule (2-3 times per week). The initial treatment can be started with an approximate dose of 20-50 IU/kg. The required dose should be titrated for each patient taking the patient's pharmacokinetic data and clinical situation into consideration. For surgical interventions, precise monitoring of the factor IX replacement therapy using the factor IX activity assay is advised.
BeneFIX is administered by IV infusion over several minutes after reconstitution of the lyophilised powder with 0.234% sodium chloride solution.

Method of calculating dose.

The method of calculating the factor IX dose is shown in the following equation.
Number of factor IX IU required (IU) = bodyweight (kg) x desired factor IX increase (% or IU/dL) x reciprocal of observed recovery (IU/kg per IU/dL).
In the presence of an inhibitor, higher doses may be required.

Patients ≥ 15 years.

In patients ≥ 15 years, on average, one IU of BeneFIX per kilogram of bodyweight increased the circulating activity of factor IX by 0.8 ± 0.2 (ranged from 0.4 to 1.4) IU/dL. The method of dose estimation is illustrated in the following example. If you use 0.8 IU/dL average increase of factor IX per IU/kg bodyweight administered, then:
Number of factor IX IU required (IU) = bodyweight (kg) x desired factor IX increase (% or IU/dL) x 1.2 IU/kg per IU/dL*.
* Reciprocal of observed recovery (IU/kg per IU/dL).

Patients < 15 years.

In patients < 15 years, on average, one IU of BeneFIX per kilogram of bodyweight increased the circulating activity of factor IX by 0.7 ± 0.3 (range 0.2 to 2.1) IU/dL. The method of dose estimation is illustrated in the following example. If you use 0.7 IU/dL average increase of factor IX per IU/kg bodyweight administered, then:
Number of factor IX IU required (IU) = bodyweight (kg) x desired factor IX increase (% or IU/dL) x 1.4 IU/kg per IU/dL*.
* Reciprocal of observed recovery (IU/kg per IU/dL).

Dosage for bleeding episodes and surgery.

Table 1 can be used to guide dosing in bleeding episodes and surgery. In the case of the haemorrhagic events listed in Table 1, the factor IX activity should not fall below the given plasma activity level (in % of normal or IU/dL) in the corresponding period.

Dosage for prophylaxis.

An appropriate dose for secondary prophylaxis has not been determined. In a clinical study of routine secondary prophylaxis in 19 previously treated patients (mean age 27.5 years, range 4 to 56 years) with moderate (1- 5% FIX activity) or severe (< 1% FIX activity) haemophilia B, the average dose was 40 IU/kg (range 13 to 78 IU/kg) twice weekly for an average of 18 months. Three patients did not experience haemorrhages, whereas the other 16 had an average of 13 haemorrhages each. In younger patients, shorter dosage intervals or higher doses may be necessary. See Method of calculating dose, above.

Elderly patients.

Clinical studies of BeneFIX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As with any patient receiving BeneFIX, dose selection for an elderly patient should be individualised.

Patients with inhibitors.

The control of bleeding episodes in patients with high titre inhibitors, typically above 5 Bethesda Units, may require an extensive factor IX infusion therapy, but might be impractical because of the very large dose needed to maintain adequate factor IX levels. If haemostasis cannot be achieved with factor IX in the presence of high titre inhibitors, the use of (activated) prothrombin complex concentrate (PCC) or activated factor VII preparation must be considered. These therapies should be directed by physicians with experience in the care of patients with haemophilia B.

Instructions for use.

Patients should follow the specific reconstitution and administration procedures provided by their physicians. Detailed instructions for preparation and administration of BeneFIX are contained in the patient insert provided in the pack.

Reconstitution.

Reconstitute BeneFIX with the diluent supplied (0.234% sodium chloride solution) from the prefilled syringe provided. Gently rotate the vial until all the powder is dissolved. After reconstitution, the solution is drawn back into the syringe. The solution should be clear and colourless. The solution should be discarded if visible particulate matter or discolouration is observed.
To reduce microbiological hazard, BeneFIX should be administered as soon as possible or within 3 hours after reconstitution. The reconstituted solution may be stored at room temperature prior to administration.

Administration (intravenous injection).

BeneFIX, nonacog alfa, should be administered using the infusion set provided in the kit, and the prefilled diluent 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. Attach the syringe to the Luer end of the infusion set and perform venipuncture.

Note.

Agglutination of red blood cells in the tubing/ syringe has been reported with the administration of BeneFIX. No adverse events have been reported in association with this observation. To minimise the risk of agglutination, it is important to limit the amount of blood entering the tubing. Blood should not enter the syringe. If red blood cell agglutination is observed in the tubing or syringe, discard all this material (tubing, syringe and BeneFIX solution) and resume administration with a new package.
After reconstitution, BeneFIX should be injected intravenously over several minutes. The rate of administration should be determined by the patient's comfort level.
BeneFIX, when reconstituted, contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of BeneFIX, including storage time elapsed in a PVC container following reconstitution. It is important that the recommendations (see Section 4.2 Dose and Method of Administration) be followed closely.

4.3 Contraindications

Because BeneFIX is produced in a Chinese hamster ovary cell line, it may be contraindicated in patients who have had a previous allergic reaction to hamster protein. BeneFIX may also be contraindicated in patients with a known history of hypersensitivity to any of the constituents of the preparation.

4.4 Special Warnings and Precautions for Use

Use with caution in the following circumstances.

Pharmacokinetic studies suggest that in vivo recovery with BeneFIX is significantly lower than that achieved with plasma derived factor IX products. Therefore, dosages are higher than those usually recommended with plasma derived products. Patients changing from a plasma derived product to BeneFIX should be aware of these differences when determining the recommended dose. Treatment should be commenced using the formulae outlined, see Section 4.2 Dose and Method of Administration and doses subsequently titrated using a factor IX activity assay.
In clinical trials with BeneFIX, the doses have been increased in several patients in order to achieve a therapeutic response, even in the absence of factor IX inhibitors. Therefore, close monitoring of factor IX plasma activity should be performed, as well as calculation of pharmacokinetic parameters such as recovery and half-life, as clinically indicated, in order to adjust doses as appropriate (see Section 4.2 Dose and Method of Administration).

Thrombosis and disseminated intravascular coagulation.

Historically, the administration of factor IX complex concentrates derived from human plasma containing factors II, VII, IX and X has been associated with the development of thromboembolic complications. Although BeneFIX contains no coagulation factor other than factor IX, the potential risk of thrombosis and disseminated intravascular coagulation (DIC) observed with other products containing factor IX should be recognised. Because of the potential risk of thromboembolic complications, caution should be exercised when administering this product to patients with liver disease, to patients postoperatively, to neonates, to patients with signs of fibrinolysis, to patients at risk of thromboembolic phenomena or to patients with DIC.
The safety and efficacy of BeneFIX administration by continuous infusion have not been established (see Section 4.8 Adverse Effects (Undesirable Effects)). There have been postmarketing reports of thrombotic events, including life threatening superior vena cava (SVC) syndrome in critically ill neonates, while receiving continuous infusion BeneFIX through a central venous catheter.
In each of these situations, the benefit of treatment with BeneFIX should be weighed against the risk of these complications.

Activity neutralizing antibodies (inhibitors).

Inhibitors have been detected in patients receiving factor IX containing products. As with all factor IX products, patients using BeneFIX should be monitored for the development of factor IX inhibitors (see Section 5.1 Pharmacodynamic Properties). Patients with factor IX inhibitors may be at an increased risk of anaphylaxis upon subsequent challenge with factor IX. Patients experiencing allergic reactions should be evaluated for the presence of inhibitor. Preliminary information suggests a relationship may exist between the presence of major deletion mutations in a patient's factor IX gene and an increased risk of inhibitor formation and of acute hypersensitivity reactions. Patients known to have major deletion mutations of the factor IX gene should be observed closely for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to the product. The safety and efficacy of BeneFIX in patients with factor IX inhibitors has not been studied. However, BeneFIX may be considered in patients with factor IX inhibitor (neutralising antibody) less than 5 Bethesda Units, who continue to respond clinically with an increase in circulating factor IX provided that BeneFIX is given in a controlled medical setting with facility to manage anaphylactic reactions. BeneFIX should be given in the dosage regimen identified.
Nephrotic syndrome has been reported following immune tolerance induction with factor IX products in haemophilia B patients with factor IX inhibitors and a history of allergic reactions. The safety and efficacy of using BeneFIX for immune tolerance induction has not been established.
In a clinical study with the original formulation of BeneFIX, which is bioequivalent to the present formulation of BeneFIX, a low titre, transient inhibitor (maximum titre 1.5 BU) developed in 1 of 65 BeneFIX patients who had previously received plasma derived products without a history of inhibitor development. This patient was able to continue treatment with BeneFIX with no anamnestic rise in inhibitor or anaphylaxis. Recovery and half-life returned to normal.
From results of the previously untreated patients study, 2 of 63 patients developed inhibitors after 7 and 15 exposure days. Both were high titre inhibitors. Both patients experienced allergic manifestations in temporal association with their inhibitor development. Twelve days after a dose of BeneFIX for a bleeding episode, one hepatitis C antibody positive patient developed a renal infarct. The relationship of the infarct to prior administration of BeneFIX is uncertain but was judged to be unlikely by the investigator. The patient continued to be treated with BeneFIX.

Hypersensitivity.

Allergic type hypersensitivity reactions, including anaphylaxis, have been reported for all factor IX products, including BeneFIX. Frequently, these events have occurred in close temporal association with the development of factor IX inhibitors. Patients should be informed of the early symptoms and signs of hypersensitivity reactions, including hives, generalised urticaria, chills (rigors), flushing, angioedema, chest tightness, laryngospasm, bronchospasm, dyspnoea, wheezing, faintness, hypotension, tachycardia, blurred vision and anaphylaxis. Patients should be advised to discontinue use of the product immediately and contact their physician and/or seek immediate emergency care, depending on the type/ severity of the reaction if any of these symptoms occur. Patients experiencing allergic reactions should be evaluated for the presence of inhibitor.
In view of the potential for allergic reactions with factor IX concentrates, the initial (approximately 10-20) administrations of factor IX should be performed under medical supervision where proper medical care for allergic reactions could be provided. If any suspected hypersensitivity reaction takes place that is thought to be related to the administration of BeneFIX, the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient.
In the case of severe allergic reactions, alternative haemostatic measures should be considered.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

Safety and efficacy have been demonstrated in previously treated and previously untreated children (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Section 5 Pharmacological Properties).

Effects on laboratory tests.

Temporary correction of partial thromboplastin time (PTT) was observed. No effect on normal prothrombin time was seen. In seven patients for whom fibrinopeptide A or prothrombin fragment 1 + 2 were measured preinfusion at 4 to 8 hours, and then daily up to 96 hours, there was no significant increase in coagulation activation.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug interaction studies have been conducted with BeneFIX. No interactions of BeneFIX with other medicinal products are known.
For information regarding physicochemical incompatibilities, see Section 4.2 Dose and Method of Administration; Section 6.2 Incompatibilities.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No investigations on impairment of fertility have been conducted.
(Category B2)
Animal reproduction studies have not been conducted with BeneFIX. It is not known whether BeneFIX can affect the course of pregnancy or cause foetal harm when given to pregnant women. BeneFIX should be administered to pregnant women only if clearly indicated.
Animal lactation studies have not been conducted with BeneFIX and there is insufficient experience with the use of factor IX products in lactating women. BeneFIX should be administered to lactating women only if clearly indicated.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. On the basis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions BeneFIX is unlikely to influence the ability to drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

The following adverse events, reported from clinical trials, with current BeneFIX and the original formulation, directly related or possibly related to therapy, are presented below by system organ class and frequency of occurrence per infusion and were recorded with a frequency less than 1%.
Uncommon ≥ 1/1,000 and < 1/100 (≥ 0.1% and < 1%).
Rare ≥ 1/10,000 and < 1/1,000 (≥ 0.01% and < 0.1%).

Immune system disorders.

Rare: hypersensitivity/ allergic reactions (including, but not limited to hives, generalised urticaria, chills, flushing, angioedema, chest tightness, laryngospasm, bronchospasm, dyspnoea, wheezing, faintness, hypotension, tachycardia, blurred vision, anaphylaxis), anaphylaxis.

Gastrointestinal disorders.

Uncommon: nausea, dysgeusia. Rare: diarrhoea, vomiting.

Cardiac disorders.

Rare: tachycardia.

Vascular disorders.

Rare: phlebitis, hypotension, flushing.

Nervous system disorders.

Uncommon: dizziness, headache. Rare: burning sensation in jaw and skull, dizziness, drowsiness, teichopsia.

Respiratory, thoracic and mediastinal disorders.

Uncommon: cough with hypoxaemia. Rare: dry cough/ sneeze, respiratory distress, chest tightness.

Skin and subcutaneous tissue disorders.

Rare: hives, rash, infusion site cellulitis, angioedema.

General disorders and administration site conditions.

Uncommon: infusion site discomfort. Rare: allergic rhinitis, lethargy, pyrexia.

Postmarketing experience.

The following postmarketing adverse reactions have been reported for BeneFIX: inadequate factor IX recovery, inadequate therapeutic response, inhibitor development (see Section 4.4 Special Warnings and Precautions for Use), anaphylaxis, dyspnoea, hypotension, thrombosis, tremor, somnolence, injection site reaction (including infusion site pruritus, infusion site erythema), infusion site pain (including infusion site irritation) and renal infarct.
The renal infarct developed in a hepatitis C antibody positive patient 12 days after a dose of BeneFIX for a bleeding episode. The relationship of the infarct to the prior administration of BeneFIX is uncertain.
The safety and efficacy of BeneFIX administration by continuous infusion have not been established (see Section 4.4 Special Warnings and Precautions for Use). There have been postmarketing reports of thrombotic events, including life threatening superior vena cava (SVC) syndrome in critically ill neonates, while receiving continuous infusion BeneFIX through a central venous catheter. Cases of peripheral thrombophlebitis, thrombosis and deep vein thrombosis (DVT) have also been reported. In some, BeneFIX was administered via continuous infusion, which is not an approved method of administration.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

No symptoms of overdose have been reported with recombinant coagulation factor IX products. In case of accidental overdosage, the development of thrombotic complications or DIC is enhanced in patients at risk for these complications. Therefore, surveillance should be carried out to detect the first signs of thrombosis and consumptive coagulopathy complications.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Factor IX is activated by factor VII/tissue factor complex in the extrinsic coagulation pathway as well as by factor XIa in the intrinsic coagulation pathway. Activated factor IX, in combination with activated factor VIII, activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, and a clot can be formed.
Factor IX is the specific clotting factor deficient in patients with haemophilia B and in patients with acquired factor IX deficiencies. The administration of BeneFIX increases plasma levels of factor IX and can temporarily correct the coagulation defect in these patients.

Clinical trials.

The efficacy of BeneFIX was assessed in 20 patients with moderately severe to severe haemophilia B (FIX:C 2% of normal) previously treated with FIX. All patients were male and their median age was 22 years (range 12-61 years). Patients were without FIX inhibitor (< 0.6 Bethesda Units) and not actively bleeding.
Fifteen patients received BeneFIX on demand, 11 whilst also receiving routine prophylactic BeneFIX. The median dose per infusion was 87 IU/kg (range 30-147 IU/kg) and the median number of infusions per patient was 5 (range 1-27). Six of the 15 followed an on demand regimen (2 later switching to routine prophylaxis). The 6 on demand patients were observed for a median of 18 weeks (range 0.1-51 weeks) and had 69 bleeds. The bleeding rate was 21.8 bleeds per year, made up of 11.4 injury related bleeds and 10.4 spontaneous bleeds per year.
Overall, 17 patients received routine BeneFIX prophylaxis and 3 received intermittent prophylaxis. The median dose per infusion was 52 IU/kg (range 14-184 IU/kg) and the median number of infusions per patient 38 (range 15-67). Of those on routine prophylaxis, three patients received BeneFIX once weekly, 10 patients twice weekly and four patients more than twice weekly. The median duration of prophylaxis was 25 weeks (range 9-40 weeks). Eleven of the 17 patients (65%) did not have a spontaneous bleed whilst on prophylaxis. The other six patients had 26 bleeds. The bleeding rate for the 17 patients was 3.1 bleeds per year, made up of 2.3 injury related bleeds and 0.8 spontaneous (plus one uncategorised) bleeds per year.
Of the 95 bleeds in the 20 patients, 81% resolved with one infusion of BeneFIX and 93% with one to two infusions. Response was rated excellent or good for 85% of infusions. The majority of bleeds were in joints (51%) or muscle/ soft tissue (38%).
After one month's BeneFIX treatment, efficacy was rated very useful in 15 of 20 patients (75%), useful in 4 (20%) and slightly useful in 1 (5%). After 6 months, it was rated very useful in 80% and useful in 20%.
One patient, with a history of septic arthritis, had a surgical procedure, left knee wash. This patient had 37 infusions of BeneFIX and no bleeding episodes. The median dose per infusion was 35 IU/kg (range 25-58 IU/kg). The efficacy of BeneFIX was rated as useful in this patient.
In clinical studies of the original formulation of BeneFIX, which is bioequivalent to the current formulation, involving a total of 128 patients (56 previously treated patients (PTPs), 63 previously untreated patients (PUPs) and the 9 patients participating only in the surgical study), more than 20 million IU were administered over a period of up to 24 months. This includes 121 HIV negative and 7 HIV positive patients. Fifty five previously treated patients were evaluated for efficacy, all of whom were treated successfully for bleeding episodes on an on demand basis or for the prevention of bleeds. Bleeding episodes that were managed successfully include haemarthroses and bleeding in soft tissue and muscle.
In a study of 28 haemophilia B patients undergoing 36 surgical procedures, including liver transplantation, splenectomy, inguinal hernia repair, orthopaedic procedures, calf debridement and complicated dental extraction, the original formulation of BeneFIX, which is bioequivalent to the current formulation, was successful in maintaining haemostasis without clinical evidence of thrombotic complications.
The previous formulation was also studied in 63 previously untreated children aged 0-14 years with haemophilia B. Fifty four children received BeneFIX on demand for haemorrhage, mostly soft tissue and muscle haemorrhage and haemarthosis. The median dose per infusion was 63 IU/kg and median exposure 19 days. Response was excellent or good in 94% of subjects. Seventy five percent of bleeding episodes resolved with one BeneFIX infusion. Thirty two children received BeneFIX for prophylaxis of bleeding at a mean dose per infusion of 73 IU/kg for a mean duration of 14 months, and 98% had an excellent or effective response. The majority of patients (75%) received more than one infusion per week. Twenty three children received BeneFIX for prophylaxis of surgical bleeding, at a median dose of 70 IU/kg for 4 days, and 97% had an excellent or good response.

5.2 Pharmacokinetic Properties

A randomised crossover study was performed using a single 75 IU/kg intravenous infusion over 10 minutes in 24 patients with moderately severe to severe haemophilia B (FIX:C 2% of normal) previously treated with coagulation factor IX (FIX) to compare the current formulation of BeneFIX to the original formulation. All patients were male and their median age was 21 years (range 12-61 years). Patients were without FIX inhibitor (< 0.6 Bethesda units) and not actively bleeding. The pharmacokinetic results demonstrated the bioequivalence of the current formulation to the original formulation. The pharmacokinetic characteristics of BeneFIX were also assessed in 23 of these patients. The mean increase in circulating FIX activity was 0.72 IU/dL per IU/kg infused (range 0.39, 1.24) and the mean plasma FIX half-life 22 h (range 13, 35). With repeated dosing over 6 months, the mean increase in circulating FIX activity after a single 75 IU/kg intravenous infusion was 0.76 IU/dL per IU/kg infused (range 0.44, 1.09) and the mean plasma FIX half-life 24 h (range 15, 48).
In a study of 19 children aged 4 to 15 years with the original formulation of BeneFIX, the mean increase in circulating FIX activity was 0.7 IU/dL per IU/kg infused (range 0.2, 2.1) and the mean plasma FIX half-life 20 h (range 14, 28).
In another randomised, crossover study with the original formulation, the in vivo recovery of FIX using BeneFIX was statistically significantly lower by 28% than the recovery using a highly purified plasma derived FIX product (pdFIX). There was no significant difference in plasma FIX half-life. Structural differences in the recombinant FIX molecule compared with pdFIX contribute to lower recovery of FIX from BeneFIX compared to pdFIX.

5.3 Preclinical Safety Data

Genotoxicity.

BeneFIX has been shown to be nonmutagenic in the Ames assay and nonclastogenic in a chromosomal aberrations assay.

Carcinogenicity.

No investigations on carcinogenicity have been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

After reconstitution of the lyophilised drug product, the concentrations of excipients are 8 mM L-histidine, 0.8% sucrose, 208 mM glycine, 0.004% polysorbate 80 and 0.234% sodium chloride.

6.2 Incompatibilities

In the absence of incompatibility studies, reconstituted BeneFIX must not be administered in the same tubing or container with other medicinal products. Only the provided infusion set should be used. Treatment failure can occur as a consequence of human coagulation factor IX adsorption to the internal surfaces of some infusion equipment (see Section 4.2 Dose and Method of Administration).

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Product as packaged for sale.

BeneFIX should be stored under refrigeration at a temperature of 2°C to 8°C. Prior to the expiration date, BeneFIX may also be stored at room temperature not to exceed 30°C for up to 6 months. The patient should make note of the date the product was placed at room temperature in the space provided on the outer carton. Freezing should be avoided to prevent damage to the diluent syringe. Do not use BeneFIX after the expiry date on the label.

Product after reconstitution.

BeneFIX does not contain a preservative. To reduce the possibility of microbiological hazard from environmental contamination, the reconstituted solution should be used as soon as possible after reconstitution or within 3 hours after reconstitution.

6.5 Nature and Contents of Container

BeneFIX 250 IU/vial, 500 IU/vial, 1000 IU/vial, 2000 IU/vial, 3000 IU/vial.
BeneFIX, nonacog alfa, is supplied in single use vials which contain nominally 250, 500, 1000, 2000 or 3000 IU per vial and a pre-filled diluent syringe containing 0.234% sodium chloride solution. The BeneFIX kit also contains a sterile infusion set, a sterile vial adapter, a sticking plaster, a sterile gauze pad and two (2) alcohol swabs. Actual factor IX activity in IU is stated on the label of each vial.
The container-closure system consists of a 10 mL USP Type I glass vial, a 20 mm OD rubber closure and a 20 mm diameter flip-off crimp seal.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

Dispose of all unused solution, empty vials, used needles and syringes in a sharps bin.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

BeneFIX nonacog alfa is a purified protein produced by recombinant DNA technology for use in therapy of factor IX deficiency, known as haemophilia B or Christmas disease. Nonacog alfa is a glycoprotein with an approximate molecular mass of 55,000 Da consisting of 415 amino acids in a single chain. It has a primary amino acid sequence that is identical to the Ala 148 allelic form of plasma derived factor IX, and has structural and functional characteristics similar to those of endogenous factor IX.
BeneFIX is produced by a genetically engineered Chinese hamster ovary (CHO) cell line that is extensively characterised and shown to be free of infectious agents. The stored cell banks are free of blood or plasma products. The CHO cell line secretes recombinant factor IX into a defined cell culture medium that does not contain any proteins derived from animal or human sources, and the recombinant factor IX is purified by a chromatography purification process that does not require a monoclonal antibody step and yields a high purity, active product. A membrane filtration step that has the ability to retain molecules with apparent molecular weights > 70,000 (such as large proteins and viral particles) is included for additional viral safety. BeneFIX is predominantly a single component by SDS polyacrylamide gel electrophoresis evaluation.

7 Medicine Schedule (Poisons Standard)

Unscheduled.

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