Consumer medicine information

Rixubis

Nonacog gamma (rch)

BRAND INFORMATION

Brand name

Rixubis

Active ingredient

Nonacog gamma (rch)

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Rixubis.

What is in this leaflet

This leaflet answers some common questions about RIXUBIS. It does not contain all of the available information. All medicines have risks and benefits. Your doctor has weighed the risks of using your medicine against the benefit that it will have for you.

It does not take the place of talking to your doctor or pharmacist.

If you have any concerns about having this medicine, ask your doctor or pharmacist.

Please read this leaflet carefully before using your medicine as it contains information about your medicine.

Keep this leaflet with your medicine. You may need to read it again.

What RIXUBIS is

RIXUBIS, nonacog gamma (rch) 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.

What RIXUBIS is used for

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

Your medicine is used to prevent and control bleeding in people with haemophilia B.

Your doctor may give you RIXUBIS when you have surgery.

Your medicine can reduce the number of bleeding episodes when used regularly (prophylaxis).

Before you use RIXUBIS

To make sure that your medicine is suitable for you, it is important to tell your doctor or pharmacist if any of the points below apply to you. If there is anything you do not understand, ask your doctor or pharmacist to explain.

Do not use RIXUBIS if you:

  • are allergic to hamsters.
  • are allergic to any ingredients in RIXUBIS (see "What is in RIXUBIS?").

What should I tell my doctor before using RIXUBIS?

You should tell your doctor if you:

  • have or have had any medical problems.
  • take any medicines, including prescription and non-prescription medicines, such as over-the-counter medicines, supplements or herbal remedies.
  • have any allergies, including allergies to hamsters.
  • are breastfeeding. It is not known if RIXUBIS passes into your milk and if it can harm your baby.
  • are pregnant or planning to become pregnant. It is not known if RIXUBIS may harm your unborn baby.
  • have been told that you have inhibitors to factor IX (because RIXUBIS may not work for you).

How RIXUBIS is given

  • Your medicine is given as an injection directly into your veins, usually by yourself, a doctor, nurse, or other trained person.
  • Your medicine contains no additives that would prevent the growth of bacteria once the powder is dissolved with sterile water. For this reason, each vial of RIXUBIS is for single use only, in one patient only. Discard any residue.
  • Your medicine should be administered as ordered by your physician. You should be trained on how to do infusions by your healthcare provider or haemophilia treatment centre. Many people with haemophilia B learn to infuse their medicine by themselves or with the help of a family member.
  • Your doctor will tell you how much medicine to use based on your weight, the severity of your haemophilia B, and where you are bleeding.
  • You may have to have blood tests done after getting your medicine to be sure that your blood level of factor IX is high enough to clot your blood.

Use only the materials provided in the box for dissolving the RIXUBIS powder and then injecting the RIXUBIS solution (see INSTRUCTIONS FOR USE).

Inject your medicine as soon as possible or within 3 hours after dissolving the powder.

Always wash your hands before doing the following procedures. Use germ-free methods during the making up procedure and during injection.

RIXUBIS must not be mixed with other injectable medicines.

If you miss/forget your injection

Proceed with the next administration immediately, and continue at regular intervals as advised by your doctor. Do not take a double dose to make up the forgotten dose.

Overdose

Immediately contact your doctor, or the Poisons Information Centre (tel: 131 126 in Australia, or tel: 0800 764 766 in New Zealand) if you inject more medicine than your doctor recommends. Do this even if there are no signs of discomfort.

While you are using RIXUBIS

Things you must do

  • See your doctor immediately if your bleeding does not stop as expected
  • Stop the infusion immediately and contact your doctor, if you experience allergic reactions such as skin rash, itching, chest discomfort, wheezing, dizziness, hives, faintness, chills, flushing, rapid heartbeat, shortness of breath and/or a swollen face
  • Always follow your doctor's instructions carefully
  • Tell all the doctors, dentists and pharmacists who are treating you that you are using RIXUBIS
  • If you are about to be started on any new medicine, tell your doctor and pharmacist that you are using RIXUBIS
  • If you become pregnant while you are using your medicine, tell your doctor.
  • Talk to your healthcare provider before traveling. Plan to bring enough medicine for your treatment during this time. It is important to obtain a written statement from your physician, explaining the reasons why you need to have this medicine and injecting devices with you, otherwise you may not be allowed to bring it into the country of travelling. Please ensure you have multiple copies of the letter if travelling to more than one country.

Things you must not do

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

Side effects

Allergic reactions may occur with your medicine.

Call your doctor or get emergency treatment right away if you get a rash or hives, itching, tightness of the throat, chest pain or tightness, difficulty breathing, lightheadedness, dizziness, nausea or fainting.

Some common side effects of RIXUBIS are stomach-flu-like symptoms (such as nausea, vomiting and stomach pain), runny nose, sore throat, headache and diarrhoea.

Tell your doctor or pharmacist about any side effects that bother you or do not go away.

These are not all the possible side effects with your medicine. You can ask your doctor or pharmacist for information that is written for healthcare professionals.

After using RIXUBIS

RIXUBIS should be stored below 30°C for the duration of its shelf life. Store in the original package in order to protect from light.

RIXUBIS contains no preservatives. Reconstituted product (what you get after dissolving the powder with the sterile water) must be used within 3 hours and cannot be stored or refrigerated. Discard any medicine left in the vial at the end of your infusion.

Keep out of the reach and sight of children.

Do not use RIXUBIS after the expiry date which is printed on the label after the word 'EXP'. The expiry date refers to the last day of that month.

Dispose of all materials, including any leftover reconstituted medicine, in an appropriate container.

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.

Instructions for use

Do not attempt to do an infusion to yourself unless you have been taught how by your healthcare provider or haemophilia center.

Always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using your medicine. If you are unsure of the procedures, please call your healthcare provider before using.

  1. Prepare a clean flat surface and gather all the materials you will need for the infusion. Check the expiration date and let the vials with the RIXUBIS concentrate and the water for injections (diluent) warm up to room temperature. Wash your hands and put on clean exam gloves. If infusing yourself at home, the use of gloves is optional.
  2. Remove caps from the RIXUBIS concentrate and diluent vials to expose the centers of the rubber stoppers.
  3. Disinfect the stoppers with an alcohol swab (or other suitable solution suggested by your healthcare provider or haemophilia center) by rubbing the stoppers firmly for several seconds and allow them to dry prior to use. Place the vials on a flat surface.
  4. Open the BAXJECT II device package by peeling away the lid, without touching the inside of the package.
Do not remove the BAXJECT II device from the package.
  1. Turn the package with the BAXJECT II device upside down and place it over the top of the diluent vial. Fully insert the clear plastic spike of the device into the center of the diluent vial's stopper by pushing straight down. Grip the package at its edge and lift it off the device. Be careful not to touch the white plastic spike.
Do not remove the blue cap from the BAXJECT II device.
The diluent vial now has the BAXJECT II device connected to it and is ready to be connected to the RIXUBIS vial.
  1. To connect the diluent vial to the RIXUBIS vial, turn the diluent vial over and place it on top of the vial containing RIXUBIS concentrate. Fully insert the white plastic spike into the RIXUBIS vial's stopper by pushing straight down. Diluent will flow into the RIXUBIS vial. This should be done right away to keep the liquid free of germs.
  2. Swirl the connected vials gently and continuously until the RIXUBIS is completely dissolved.
Do not shake.
The RIXUBIS solution should look clear and colorless. If not, do not use it and notify Baxter immediately.
  1. Take off the blue cap from the BAXJECT II device and connect the syringe by screwing the syringe clockwise into the BAXJECT II device.
Be careful to not inject air.
  1. Turn over the connected vials so that the RIXUBIS vial is on top. Draw the RIXUBIS solution into the syringe by pulling back the plunger slowly. Disconnect the syringe from the vials.
  2. If you are using more than one vial of RIXUBIS, the contents of more than one vial may be drawn into the same syringe.
Make sure you mix each vial of RIXUBIS with the water for injections that is provided in the box (Following Steps 1-9).
You will need a separate BAXJECT II device to mix each additional vial of RIXUBIS.
  1. Attach the infusion needle to the syringe using a winged (butterfly) infusion set, if available. Point the needle up and remove any air bubbles by gently tapping the syringe with your finger and slowly and carefully pushing air out of the syringe and needle.
  2. Apply a tourniquet and get the infusion site ready by wiping the skin well with an alcohol swab (or other suitable solution suggested by your healthcare provider or haemophilia center).
  3. Insert the needle into the vein and remove the tourniquet. Slowly infuse the RIXUBIS.
Do not infuse any faster than 10 mL per minute.
  1. Take the needle out of the vein and use sterile gauze to put pressure on the infusion site for several minutes.
Do not recap the needle.
Place it with the used syringe in a hard-walled Sharps container for proper disposal.
  1. Dispose of the used vials and BAXJECT II system in your hard-walled Sharps container without taking them apart. Do not dispose of these supplies in ordinary household trash.
  2. Remove the peel-off label from the RIXUBIS vial and place it in your logbook. Clean any spilled blood with a freshly prepared mixture of 1 part bleach and 9 parts water, soap and water, or any household disinfecting solution.

Important: Contact your healthcare provider or local haemophilia treatment center if you experience any problems.

Product Description

What RIXUBIS looks like?

RIXUBIS comes as a white or off-white powder in a glass vial.

Each vial of your medicine is accompanied by a glass vial containing water for injections for dissolving the powder. The package also comes with a device known as the BAXJECT II which is used to transfer the sterile water in the glass vial to the powder vial.

An ancillary set containing alcohol swabs, adhesive bandages, an infusion set, a syringe and a butterfly needle may be supplied with your medicine.

What is in RIXUBIS?

The active substance in RIXUBIS is nonacog gamma. Five strengths, i.e. 250 IU, 500 IU, 1000 IU, 2000 IU and 3000 IU of RIXUBIS are commercially available.

Inactive ingredients: histidine, sodium chloride, calcium chloride dihydrate, mannitol, sucrose, polysorbate 80.

Supplier

RIXUBIS is supplied in Australia by:

Shire Australia Pty Limited
(now part of Takeda)
Level 39, 225 George Street
Sydney NSW 2000
Australia
Telephone: 1800 012 612

RIXUBIS is supplied in New Zealand by:

Shire New Zealand Limited
(now part of Takeda)
C/o Crowe Horwath
Level 29, 188 Quay Street
Auckland Central
Auckland
Telephone: 0508 169 077

Date of preparation

This leaflet was prepared in September 2019.

RIXUBIS is a trademark of Baxalta Incorporated, a wholly-owned, indirect subsidiary of Shire plc.

Shire and the Shire Logo are trademarks of Shire Pharmaceutical Holdings Ireland Limited or its affiliates, each a Takeda company.

Published by MIMS November 2019

BRAND INFORMATION

Brand name

Rixubis

Active ingredient

Nonacog gamma (rch)

Schedule

Unscheduled

 

1 Name of Medicine

Recombinant Coagulation Factor IX (rFIX), Nonacog gamma (rch), rFIX.

6.7 Physicochemical Properties

The recombinant human factor IX (rFIX) is a glycoprotein consisting of 415 amino acids. Rixubis is synthesised by a genetically engineered Chinese hamster ovary (CHO) cell line. No exogenous materials of human or animal origin are employed in the manufacture, purification, or formulation of the final product. The growth medium is chemically defined and the downstream process does not use monoclonal antibodies for the purification of Rixubis. The production process also includes two independent viral removal/inactivation steps: solvent detergent treatment and nanofiltration.
Biological potency is determined by a one-stage clotting assay, which employs a factor IX concentrate standard that is referenced to the World Health Organization (WHO) International Standard for factor IX concentrates.

CAS number.

CAS No: 181054-95-5.

2 Qualitative and Quantitative Composition

The product is available in the following strengths: 250 IU, 500 IU, 1000 IU, 2000 IU, and 3000 IU.
The product concentration differs for each strength as every strength is reconstituted with the accompanying 5 mL of water for injections.
The specific activity of rFIX is ≥ 200 IU factor IX per mg.

Composition.

See Table 1.
The amounts of the inactive ingredients are constant in all strengths. For the full list of excipients, see Section 6.1 List of Excipients, Table 13.

3 Pharmaceutical Form

Powder and solvent for solution for injection.

Appearance.

White, lyophilised powder and diluent for solution, for intravenous administration.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Rixubis contains recombinant coagulation factor IX.

Mechanism of action.

Recombinant coagulation factor IX is a single chain glycoprotein that is a member of the serine protease family of vitamin K-dependent coagulation factors. Recombinant coagulation factor IX is a recombinant DNA-based protein therapeutic which has structural and functional characteristics comparable to endogenous factor IX. Factor IX is activated by factor VIIa/tissue factor complex in the extrinsic pathway and 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 into fibrin, and a clot can be formed. Factor IX activity is absent or greatly reduced in patients with haemophilia B, and substitution therapy may be required.
Haemophilia B is an X chromosome-linked recessive congenital disorder of blood coagulation due to decreased levels or complete lack of factor IX and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. Replacement therapy increases the plasma level of factor IX, providing a temporary correction of the factor deficiency and the bleeding tendency.

Clinical trials.

Prophylaxis and control of bleeding in PTPs ≥ 12 years of age.

The efficacy of Rixubis has been evaluated in the open-label, uncontrolled part of a combined phase 1/3 study, in which a total of 73 male, previously treated patients (PTPs) between 12 and 59 years of age received Rixubis either for the prophylaxis and/or for the treatment of bleeding episodes on an on-demand basis. PTPs were defined as subjects who were exposed to a factor IX-containing product on ≥ 150 days. All subjects had severe (factor IX level < 1%) or moderately severe (factor IX level ≤ 2%) haemophilia B. Subjects with a history of or a detectable FIX inhibitor ≥ 0.6 BU, a history with severe allergic reactions following exposure to FIX, evidence of a severe chronic liver disease (INR > 1.4), impaired renal function, a CD4 count < 200 cells/mm3 or any haemostatic effect other than haemophilia B were excluded from participation. Fifty-nine (59) PTPs received Rixubis for prophylaxis. Fifty six (56) of these PTPs who received Rixubis for a minimum of 3 months, were included in the efficacy evaluation for prophylaxis (see Tables 4 and 5). An additional 14 PTPs received Rixubis for treatment of bleeding episodes only. Subjects in the on-demand cohort had to have at least 12 documented bleeding episodes requiring treatment within 12 months prior to enrolment. The mean treatment duration in the on-demand cohort was 3.5 ± 1.00 months (median 3.4, ranging from 1.2 to 5.1 months), the mean annualized bleeding rate (ABR) was 33.9 ± 17.37 ranging from 12.9 to 73.1.

Prophylaxis.

The mean ABR on prophylaxis for all bleeds was 4.3, for spontaneous bleeds 1.7 and for joint bleeds 2.9 (see Table 4).

Comparison with historical control.

The mean total ABR of a historical control was compared with the mean total ABR resulting from twice-weekly treatment with Rixubis. The historical control is based on a meta-analysis of data from 12 studies published from 1976 to 2011 with a total of 276 hemophilia B patients (children and adults) treated on-demand with various factor IX products for a mean duration of 19.6 months. The mean total ABR was 20.0 (SD 39.4; 95% CI 15.3; 24.6, whereas the mean total ABR in the Rixubis prophylactic cohort (based on data of an interim analysis with n = 56 with at least 3 months treatment), was 4.20 ± 5.75 (95% CI 2.66; 5.74). The difference was statistically significant (p < 0.001) with a reduction of total ABR by 79%.

Treatment of bleeding episodes.

A total of 249 bleeding episodes were treated with Rixubis, of which 197 were joint bleeds and 52 non-joint bleeds (soft tissue, muscle, body cavity, intracranial and other). Of a total of 249 bleeding episodes, 163 were moderate, 71 were minor, and 15 were major. Treatment was individualized based on the severity, cause and site of bleed. Of the 249 bleeding episodes, the majority (211; 84.7%) were treated with 1-2 infusions.
Haemostatic efficacy at resolution of bleed was rated excellent or good in 95.4% of all treated bleeding episodes. No bleeding episode had an efficacy rating of "none".

Prophylaxis and control of bleeding in PTPs < 12 years of age.

The efficacy of Rixubis has been evaluated in a combined phase 2/3 study, in which a total of 23 male (PTPs) between 1.8 and 11.8 years (median age 7.10 years) with 11 patients < 6 years, received Rixubis for prophylaxis and control of bleeding episodes. PTPs were defined as subjects who were exposed to a factor IX-containing product on ≥ 150 days for subjects aged 6 to < 12 years, and on ≥ 50 days for subjects aged < 6 years. All subjects had severe (factor IX level < 1%) or moderately severe (factor IX level ≤ 2%) hemophilia B. Subjects with a history of or a detectable FIX inhibitor ≥ 0.6 BU, a history of severe allergic reactions following exposure to FIX, evidence of severe chronic liver disease (INR > 1.4), impaired renal function, a CD4 count < 200 cells/mm3 or any hemostatic effect other than hemophilia B were excluded from participation. All 23 subjects received prophylactic treatment with Rixubis for a minimum of 3 months and were included in the efficacy evaluation for prophylaxis (see Table 5).

Treatment of bleeding episodes in PTPs < 12 years of age.

A total of 26 bleeding episodes were treated with Rixubis, of which 23 bleeds were due to injury, 2 spontaneous and 1 of unknown origin; 19 bleeds were non-joint (soft tissue, muscle, body cavity, intracranial and other) and 7 were joint bleeds of which 1 was a bleed into a target joint. Of the 26 bleeding episodes, 15 were minor, 9 moderate, and 2 major. Treatment was individualized based on the severity, cause and site of bleed. The majority (23; 88.5%) were treated with 1-2 infusions. The actual breakdown was (15; 57.7%) received 1 infusion, (8; 30.8%) received 2 infusions, and (3; 11.5%) were treated with 3 infusions. Hemostatic efficacy at resolution of a bleed was rated excellent or good in 96.2% of all treated bleeding episodes.

Perioperative management.

The safety and efficacy in the perioperative setting was evaluated in an ongoing phase 3 prospective, open-label, uncontrolled, multicentre study in male PTPs with severe and moderately severe haemophilia B using Rixubis. The per-protocol efficacy analysis includes 13 surgeries performed in 13 patients between 19 and 54 years of age undergoing major or minor surgical, dental or other surgical invasive procedures. Ten (10) procedures were major including 6 orthopaedic and 1 dental surgery. Three procedures including 2 dental extractions, were considered minor.
Patients undergoing major surgeries had to perform a pharmacokinetic (PK) evaluation. All patients were dosed based on their most recent individual incremental recovery. The recommended initial loading dose of Rixubis was to ensure that during surgery, factor IX activity levels of 80-100% for major surgeries and 30-60% for minor surgeries was maintained.
Rixubis was administered by bolus infusions.
Haemostasis was maintained throughout the study duration.
Table 6 shows the types of surgical procedures and the results of the assessment of the haemostatic response at various points in time.

Thrombogenicity.

In all studies subjects were monitored for the presence of thrombosis. There was no clinical evidence of thrombotic complications in any of the subjects.
Out-of-range values for thrombogenicity markers (thrombin-antithrombin III [TAT], prothrombin fragment 1.2, and D-dimer), determined during the pharmacokinetic portion of the combined phase 1/3 pivotal study (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties), did not reveal any pattern indicative of clinically relevant thrombogenicity with either Rixubis or the comparator, and were not associated with adverse events.

5.2 Pharmacokinetic Properties

Previously treated patients ≥ 12 years of age.

A randomized, blinded, controlled, crossover pharmacokinetic study of Rixubis and a comparator was conducted in non-bleeding male subjects (≥ 15 years of age) as part of the combined phase 1/3 pivotal study. The subjects received either of the products as a single IV infusion. The mean (± SD) and median dose of Rixubis in the per protocol analysis set (n = 25) were 74.69 ± 2.37 and 74.25 IU/kg, respectively, with a range of 71.27 to 79.38 IU/kg. The mean and median doses of the comparator were 74.83 ± 2.51 and 74.92 IU/kg, respectively, with a range of 70.12 to 80 IU/kg. The pharmacokinetic parameters were calculated from factor IX activity measurements in blood samples obtained up to 72 hours following each infusion.
The pharmacokinetic evaluation was repeated for Rixubis in an open-label, uncontrolled study with Rixubis in male subjects who participated in the initial PK crossover study and had received prophylaxis with Rixubis for 26 ± 1 weeks (mean ± SD) and accumulated at least 30 exposure days (EDs) to Rixubis. The Rixubis dose range in the repeat pharmacokinetics study was 64.48 to 79.18 IU/kg (n = 23).
Pharmacokinetic parameters for evaluable subjects (per-protocol analysis) are presented in Table 7.
The 90% confidence intervals for the AUC0-72 h/dose and AUC0-72 h were within the margins of equivalence defined as 80% to 125%.
Incremental recovery 30 minutes after infusion was determined for all subjects in the combined phase 1/3 study at exposure day 1, at their week 5, 13, and 26 visits, and at the time of study completion or termination, if it did not coincide with the week 26 visit. The data demonstrate that the incremental recovery is consistent over time. See Table 8.

Previously treated patients < 12 years of age.

All 23 male subjects underwent an initial pharmacokinetic evaluation of Rixubis in a non-bleeding state as part of the combined phase 2/3 pediatric study. Subjects were randomized to one of two blood sampling sequences to reduce the burden of frequent blood draws on the individual subjects. The mean (± SD) and median dose of Rixubis in the full analysis set (n = 23) was 75.50 ± 3.016 and 75.25 IU/kg, respectively, with a range of 70.0 to 83.6 IU/kg. The pharmacokinetic parameters were calculated from factor IX activity measurements in blood samples obtained up to 72 hours following the infusion.
Pharmacokinetic parameters for all subjects (full analysis set) are presented in Table 9.
Incremental recovery 30 minutes after infusion was determined for all subjects in the combined phase 2/3 study at the initial pharmacokinetic evaluation (exposure day 1), at week 5, 13, and 26 visits, and at the time of study completion or termination, if it did not coincide with the week 26 visit. The data demonstrate that the incremental recovery is consistent over time across all pediatric age groups. See Tables 10, 11 and 12.

5.3 Preclinical Safety Data

Studies on carcinogenesis and mutagenesis of Rixubis, coagulation factor IX (recombinant), were not conducted, since no risk is anticipated for biotechnology-derived pharmaceuticals such as coagulation factor IX (recombinant).

4 Clinical Particulars

4.1 Therapeutic Indications

Rixubis is indicated for:
routine prophylaxis of bleeding episodes in patients with haemophilia B;
treatment and prevention of bleeding episodes in patients with haemophilia B (congenital factor IX deficiency);
peri-operative management in patients with haemophilia B.

4.3 Contraindications

Rixubis is contraindicated in patients with known hypersensitivity to active substance, to excipients, or to hamster protein.

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions.

Hypersensitivity has been reported with Rixubis. Anaphylaxis and other hypersensitivity reactions to any type of factor IX concentrate are possible. Patients and/or their caregivers should be informed of the early signs of hypersensitivity reactions. They should be advised to discontinue use of the product immediately and contact their physician if such symptoms occur. The risk is highest during the early phases of initial exposure to factor IX concentrates in previously untreated patients (PUPs), in particular in patients with high-risk gene mutations.
There have been reports in the literature showing an association between the occurrence of a factor IX inhibitor and allergic reactions, in particular in patients with a high risk gene mutation. Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor.
In case of shock, the current medical standards for shock treatment should be observed.

Inhibitors - nephrotic syndrome.

Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX.
Patients using Rixubis should be regularly evaluated for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. If expected plasma factor IX activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor IX inhibitor concentration should be performed.
If a patient develops an inhibitor, it is recommended that a specialized haemophilia centre be contacted.
In patients with high titer factor IX inhibitors, Rixubis therapy may not be effective and other therapeutic options should be considered.
Patients with factor IX inhibitors are at an increased risk of severe hypersensitivity reactions or anaphylaxis if re-exposed to factor IX.
Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors. The safety and efficacy of using Rixubis for immune tolerance induction has not been established.

Thromboembolism, DIC, fibrinolysis.

The use of factor IX products has been associated with the development of thromboembolic complications. Therefore, the use of factor IX-containing products may be potentially hazardous in patients with disseminated intravascular coagulation (DIC) and in patients with signs of fibrinolysis.
Clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing, in particular when administering this product to patients with liver disease, to patients peri- and postoperatively, to newborn infants, or to other patients at risk for thromboembolic events or DIC.
In patients with DIC or those at risk for DIC or thromboembolic events, the benefit of treatment with Rixubis should be weighed against the risk of these complications.

Use in the elderly.

Clinical studies of Rixubis did not include subjects aged 65 and over. It is not known whether they respond differently from younger subjects. As for all patients, dose selection for an elderly patient should be individualised.

Monitoring laboratory tests.

Monitor factor IX activity levels by the one-stage clotting assay to confirm that adequate factor IX levels have been achieved and maintained, when clinically indicated (see Section 4.2 Dose and Method of Administration).
Monitor for the development of inhibitors if expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with the recommended dose of Rixubis. Assays used to determine if factor IX inhibitor is present should be titred in Bethesda Units (BUs).

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interactions of recombinant coagulation factor IX products with other medicinal products are known.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of Rixubis on fertility have not been established.
(Category B2)
Category B2: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.
There are no data from the use of Rixubis in pregnant or lactating women. Healthcare providers should balance the potential risks and only prescribe Rixubis if clearly needed.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions from clinical trials.

The following adverse reactions have been identified during clinical development of Rixubis from 2 completed studies and 2 ongoing studies* with 99 unique, male previously treated patients PTPs with haemophilia B receiving a total of 14,018 infusions. See Table 3.

Immunogenicity.

Of the 99 PTPs exposed to Rixubis during clinical development, none developed inhibitory or treatment-related# total binding antibodies# to factor IX or antibodies to Chinese hamster ovary (CHO) proteins. One subject had a positive titer for rfurin that was not present when checked at a later time point and was therefore considered transient. No clinical adverse findings were observed in this subject.
#Defined as a more than 2 dilution steps increase in specific titer compared to prestudy level.

Post-marketing adverse reactions.

The following adverse reactions have been reported, listed by MedDRA (Version 17.1) System Organ Class (SOC), then by Preferred Term in order of severity.

Immune system disorders.

Hypersensitivity (including symptoms such as dyspnoea, pruritus).

Skin and subcutaneous tissue disorders.

Urticaria, rash.

Class reactions.

Disseminated intravascular coagulation, embolism (e.g. pulmonary embolism, venous thrombosis, arterial thrombosis).
Anaphylactic reaction or hypersensitivity reactions (including symptoms such as angioedema, chest discomfort, hypotension, lethargy, nausea, vomiting, paraesthesia, restlessness, wheezing, dyspnoea).
See Section 4.4 Special Warnings and Precautions for Use.

Reporting an adverse event.

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 http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

General.

Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia.
It is recommended that prescribed doses of Rixubis are expressed as 'International Units' (written in full) of factor IX.
Patients and their caregivers should be adequately trained in the correct administration technique before self-administration of Rixubis in a home treatment setting can be considered.
The dosage and duration of the substitution therapy depend on the severity of the factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition, age and pharmacokinetic parameters of factor IX, such as incremental recovery and half-life.
To ensure that the desired factor IX activity plasma level has been attained, careful monitoring using an appropriate factor IX activity assay is advised and, if necessary, appropriate adjustments to the dose and the frequency of repeated infusions should be performed. (See Section 4.4 Special Warnings and Precautions for Use).

Inhibitors.

Patients using Rixubis should be monitored for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. If expected plasma factor IX activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor IX inhibitor concentration should be performed. (See Section 4.4 Special Warnings and Precautions for Use).

Dosage.

A guide for calculating the dose for treatment of bleeding episodes is provided below:
Number of factor IX IU required = body weight (in kg) x desired factor IX increase (%) or (IU/dL) x reciprocal of observed recovery (dL/kg).

Patients ≥ 12 years of age.

The calculation of the required dose of Rixubis can be based on the empirical finding that 1 IU Rixubis per kg body weight is expected to increase the circulating level of factor IX by 0.9 IU/dL of plasma (0.9% of normal) (range from 0.5 to 1.4 IU/dL).
For an incremental recovery of 0.9 IU/dL of plasma (0.9% of normal), the dose is calculated as follows:
Number of factor IX IU required = body weight (in kg) x desired factor IX increase (%) or (IU/dL) x 1.1 dL/kg.

Patients < 12 years of age.

The calculation of the required dose of Rixubis can be based on the empirical finding that 1 IU Rixubis per kg body weight is expected to increase the circulating level of factor IX by 0.7 IU/dL of plasma (0.7% of normal) (range from 0.31 to 1.0 IU/dL).
For an incremental recovery of 0.7 IU/dL of plasma (0.7% of normal), the dose is calculated as follows:
Number of factor IX IU required = body weight (in kg) x desired factor IX increase (%) or (IU/dL) x 1.4 dL/kg.
Due to the wide range of individual differences in incremental recovery, it is recommended to base the calculation of the required dose on the patient's individual incremental recovery using serial factor IX activity assays.
Doses administered should be titrated to the patient's clinical response and individual pharmacokinetics, in particular incremental recovery and half-life.

Treatment of bleeding episodes and peri-operative management.

In the case of the following haemorrhagic events, the factor IX activity should not fall below the plasma factor IX activity levels (in % of normal or in IU/dL) in the corresponding period. See Table 2.
Careful monitoring of replacement therapy is especially important in cases of major surgery or life-threatening haemorrhages.

Routine prophylaxis.

Rixubis can be administered for long-term prophylaxis against bleeding in patients with severe and moderately severe haemophilia B. The recommended dose for previously treated patients (PTPs) ≥ 12 years of age is 40 to 60 IU/kg twice weekly. The recommended dose for patients < 12 years of age is 40 to 80 IU/kg twice weekly. Shorter dosage intervals or higher doses may become necessary depending upon the individual patient's pharmacokinetics, age, bleeding phenotype, and physical activity.

Method of administration.

Rixubis is administered by intravenous (IV) infusion.
Administer Rixubis at room temperature using a rate that ensures the comfort of the patient, up to a maximum of 10 mL/min.
Do not administer Rixubis by continuous infusion.
Only use plastic syringes with this product.

Instructions for use.

Administer Rixubis by intravenous (IV) infusion after reconstitution.
Initiate treatment under the supervision of a physician experienced in the treatment of haemophilia and continue treatment under supervision for a period of time. (See Section 4.4 Special Warnings and Precautions for Use, Hypersensitivity reactions).
Inspect parenteral drug products for particulate matter and discolouration prior to administration, whenever solution and container permit. The solution should be clear and colourless in appearance. If not, do not use the solution and notify Shire.
Administer Rixubis at room temperature within 3 hours of reconstitution. Rixubis contains no antimicrobial preservative. It is for single use in one patient only. Discard any unused product.
Perform reconstitution, product administration, and handling of the administration set and needles with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted Rixubis, in an appropriate container.
The procedures below are provided as general guidelines for the preparation and reconstitution of Rixubis. Always work on a clean surface and wash your hands before performing the following procedures.
1. Use aseptic technique during reconstitution procedure.
2. Allow the Rixubis vial (dry factor concentrate) and water for injections vial (diluent) to reach room temperature.
3. Remove caps from the factor concentrate and diluent vials.
4. Cleanse stoppers with germicidal solution and allow to dry prior to use. Place the vials on a flat surface.
5. Open the Baxject II device package by peeling away the lid, without touching the inside. Do not remove the device from the package. Note that the Baxject II device is intended for use with a single vial of Rixubis and water for injections; therefore, reconstituting and withdrawing a second vial into the syringe requires a second Baxject II device.
6. Turn the package over. Press straight down to fully insert the clear plastic spike through the diluent vial stopper.
7. Grip the Baxject II package at its edge and pull the package off the device. Do not remove the blue cap from the Baxject II device. Do not touch the exposed white plastic spike.
8. Turn the system over so that the diluent vial is on top. Quickly insert the white plastic spike fully into the Rixubis vial stopper by pushing straight down. The vacuum will draw the diluent into the Rixubis vial.
9. Swirl gently until Rixubis is completely dissolved. Do not refrigerate after reconstitution. Use within 3 hours of reconstitution.
10. Remove the blue cap from the Baxject II device. Connect the syringe to the Baxject II device. Do not inject air.
11. Turn the system upside down (factor concentrate vial now on top). Draw the factor concentrate into the syringe by pulling the plunger back slowly.
12. Disconnect the syringe; attach a suitable needle and inject intravenously as instructed by bolus infusion. If a patient is to receive more than one vial of Rixubis, the contents of multiple vials may be drawn into the same syringe.
13. Maximum infusion rate of 10 mL/min.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

No symptoms of overdose have been reported.
For information on the management of overdose, contact the Poisons Information Centre telephone: 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

Unscheduled.

6 Pharmaceutical Particulars

6.1 List of Excipients

The amounts of the inactive ingredients are constant in all strengths.
See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

This product must not be mixed with other medicinal products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the ARTG. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Storage.

Store below 30°C.

Storage after reconstitution.

Chemical and physical in-use stability has been demonstrated for 3 hours at temperatures up to 30°C.
Do not use beyond the expiration date printed on the vial or carton.

6.5 Nature and Contents of Container

Container type.

Rixubis is a white or almost white lyophilised powder which is supplied in a single-dose Type I glass vial: 250 IU, 500 IU, 1000 IU, 2000 IU or 3000 IU. The vial is closed with a butyl rubber stopper. The components of this product are latex-free.
Each kit also contains 5 mL of water for injections in a Type I glass vial and Baxject II Transfer device.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes