PACKAGE LEAFLET: INFORMATION FOR THE USER

FIXNOVE 600 IU

Powder and solvent for solution for injection or infusion
human blood coagulation factor IX
Please read this leaflet carefully before using this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, because it could be harmful.
If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

What FIXNOVE is and what it is used for
What you need to know before using FIXNOVE
How to use FIXNOVE
Possible side effects
How to store FIXNOVE
Contents of the pack and other information

1. What FIXNOVE is and what it is used for

FIXNOVE is a coagulation factor IX concentrate. It replaces the missing or poorly functioning factor IX in patients with haemophilia B. Haemophilia B is a hereditary, sex-linked blood coagulation disorder caused by reduced levels of factor IX, leading to severe bleeding into joints, muscles, or internal organs, either spontaneously or following accidental or surgical trauma.
Administration of FIXNOVE enables temporary correction of the factor IX deficiency and reduces the tendency to bleed.
FIXNOVE is used for the treatment and prophylaxis of bleeding episodes in patients with congenital haemophilia B.
FIXNOVE is indicated for all age groups starting from children above 6 years of age.
Available data are insufficient to recommend the use of FIXNOVE in children under 6 years of age.

2. What you should know before using FIXNOVE

Do not use FIXNOVE

if you are allergic to human coagulation factor IX or to any of the other ingredients of this medicine (listed in section 6).
if you have a known allergic reaction to heparin, or if you have previously experienced an abnormal decrease in blood cells involved in clot formation following heparin administration ( heparin-induced thrombocytopenia ).

After appropriate treatment of these conditions, FIXNOVE should only be used in cases of
life-threatening bleeding episodes.
Warnings and precautions
Talk to your doctor or pharmacist before using FIXNOVE.
In case of allergic reactions:
There is a rare possibility of experiencing a severe and sudden allergic reaction (anaphylactic reaction)
to FIXNOVE.
If any of the following symptoms occur, stop the infusion immediately
and contact your doctor immediately . These symptoms may be early signs of anaphylactic shock and
require prompt emergency intervention.

skin flushing
rash
development of red, raised skin lesions (urticaria)
generalized itching
swelling of the lips and tongue
difficulty breathing (dyspnea)
difficulty inhaling/exhaling due to airway constriction (respiratory distress)
chest tightness
general feeling of malaise
dizziness
drop in blood pressure
loss of consciousness

When monitoring is required:

Your doctor will regularly perform blood tests to ensure that the current dose is adequate and that you are receiving sufficient factor IX.
To promptly detect possible complications, your doctor will monitor you closely, especially if you are receiving high doses of FIXNOVE or if you have a predisposition to thrombosis. In such cases, you may also be administered a lower level of factor IX, the active substance in FIXNOVE. In case of persistent bleeding:
If your bleeding is not controlled with FIXNOVE, contact your doctor immediately . You may have developed factor IX inhibitors. Factor IX inhibitors are antibodies in the blood that counteract the activity of factor IX, thereby reducing the effectiveness of FIXNOVE in treating bleeding. Your doctor will perform the necessary tests to confirm this.
There may be a link between the development of factor IX inhibitors and allergic reactions. Patients with factor IX inhibitors may have an increased risk of severe and sudden allergic reactions (anaphylaxis). Therefore, patients who develop an allergic reaction should be tested for the presence of a factor IX inhibitor.

Inform your doctor if you have liver or heart disease or if you have recently undergone major surgery, as there is an increased risk of blood coagulation complications.
Information on safety regarding transmissible agents
For medicines derived from human blood or plasma, several measures are taken to prevent transmission of infections to patients. These measures include:

careful selection of blood and plasma donors to exclude individuals at risk of carrying infections,
testing of each donation and plasma pools for signs of viruses/infections,
inclusion of manufacturing procedures capable of inactivating or removing viruses.

Nevertheless, when administering medicinal products derived from human blood or plasma, it is not possible to completely exclude the risk of transmitting infections.
This also applies to unknown or emerging viruses and other types of infections.
The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus, and against the non-enveloped hepatitis A virus.
The measures taken may have limited effectiveness against non-enveloped viruses such as parvovirus B19 [a virus causing skin redness (erythema infectiosum)].
Parvovirus B19 infection may be severe in pregnant women (fetal infection) and in individuals with immunodeficiency or certain types of anemia (e.g. sickle cell anemia or hemolytic anemia).
Your doctor may recommend that you consider vaccination against hepatitis A and B if you are undergoing regular/repeated treatment with human plasma-derived products.
It is strongly recommended that, each time FIXNOVE is administered, the name and batch number of the medicine be recorded to maintain traceability of the batches used.
Children
Available data are insufficient to recommend the use of FIXNOVE in children under 6 years of age.
Other medicines and FIXNOVE
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
No interactions of FIXNOVE with other medicines are known.
Pregnancy and breastfeeding
Hemophilia B in women is very rare. Therefore, there is no experience regarding the use of FIXNOVE
during pregnancy and breastfeeding.
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor before using this medicine. Your doctor will decide whether you can use FIXNOVE during pregnancy and breastfeeding.
Driving and using machines
No effects on the ability to drive vehicles or operate machinery have been observed.
FIXNOVE contains sodium chloride and sodium citrate
FIXNOVE 600 IU contains 20 mg of sodium (a component of table salt) per vial.
This corresponds to 1% of the maximum daily recommended dietary intake for an adult.

3. How to use FIXNOVE

Your treatment must be initiated and supervised by physicians experienced in the management of haemophilia B.
Your doctor will determine the appropriate dose for you, calculating it according to your individual needs. Contact your doctor if you feel that the effect of FIXNOVE is too strong or too weak.

Use in children
Available data are insufficient to recommend the use of FIXNOVE in children under 6 years of age.

Monitoring by the doctor
Your doctor will perform appropriate laboratory tests at regular intervals to ensure that adequate factor IX levels in the blood have been achieved. This is particularly important in the case of major surgical procedures or life-threatening bleeding episodes.

Patients who develop inhibitors
If the desired plasma factor IX level is not achieved despite administration of an appropriate dose, or if bleeding does not stop, inhibitors may be present. The presence of inhibitors will be checked by your doctor through appropriate tests.
In case inhibitors develop, contact a specialized haemophilia centre.
If you have developed factor IX inhibitors, you may require higher amounts of FIXNOVE to control bleeding. If this dose fails to control the bleeding, your doctor will consider alternative therapy. Do not increase the dose of FIXNOVE to control bleeding without first consulting your doctor.

Frequency of administration
Your doctor will explain the frequency and intervals of FIXNOVE administration, tailored to your individual needs and based on your response to FIXNOVE.

Route and/or method of administration
FIXNOVE is administered slowly into a vein (intravenously) after reconstituting the solution with the solvent provided in the package.
FIXNOVE must not be mixed with other medicinal products before administration, as this may compromise the efficacy and safety of the product.
Follow your doctor's instructions carefully.
The rate of administration depends on your comfort level and must not exceed 2 ml per minute.

Use only the administration set provided in the package. If other sets are used, FIXNOVE may adhere to the inside of the infusion set, resulting in an incorrect dose being administered.
If you are also receiving other medicinal products through the same venous access, the access must be flushed with a suitable solution, such as saline, before and after the administration of FIXNOVE.
Reconstitute FIXNOVE only immediately before use, and use the solution immediately. (The solution contains no preservatives.) The infusion must be completed within 3 hours after reconstitution.
The solution for injection should be clear or slightly whitish (opalescent). Do not use solutions that appear cloudy or contain visible particles.
Any unused reconstituted product must be properly disposed of.

Reconstitution of the lyophilisate to prepare a solution for injection:
Ensure that you prepare the solution under the cleanest and most sterile conditions possible!

Bring the vial with intact rubber stopper containing the solvent (sterile water for injection) to room temperature (max. +37°C).
Remove the protective caps from the rubber-stoppered vials of concentrate and solvent (Fig. A), and disinfect the rubber stoppers of both vials.
Remove the protective cap from one end of the transfer needle provided in the package by twisting and pulling it off. Insert the exposed needle through the rubber stopper of the solvent vial (Fig. B and C).
Remove the protective cap from the other end of the transfer needle, taking care not to touch the exposed part.
Invert the solvent vial over the concentrate vial and insert the free end of the transfer needle through the rubber stopper of the concentrate vial (Fig. D). The solvent will be drawn into the powder vial by vacuum.
After all the solvent has been transferred into the concentrate vial, separate the two vials by removing the transfer needle from the concentrate vial (Fig. E). Gently swirl the powder vial to accelerate dissolution.
Once reconstitution is complete, insert the vent needle provided in the package (Fig. F); any foam present will dissipate. Remove the vent needle.

Injection / Infusion:
Ensure that you prepare the solution under the cleanest and most sterile conditions possible!

Remove the protective cap from the filter needle provided in the package by twisting and pulling it off, and attach the filter needle to the single-use sterile syringe. Draw the solution into the syringe (Fig. G).
Disconnect the filter needle from the syringe and inject the solution slowly intravenously (maximum injection rate 2 ml/min) using the infusion set provided in the package (or the single-use needle provided).

If administered by infusion, a single-use butterfly infusion set with an appropriate filter must be used.

Duration of treatment
Replacement therapy with FIXNOVE is generally a lifelong treatment.

If you use more FIXNOVE than you should
Contact your doctor. Symptoms of factor IX overdose have not been reported.

If you forget to use FIXNOVE

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

If you stop using FIXNOVE
Do not stop treatment with FIXNOVE without first consulting your doctor.
If you have any doubts about how to use this medicine, contact your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody experiences them.
If you experience any of the following serious side effects, inform your doctor immediately.

severe allergic reaction (anaphylactic reaction). If you experience any of the following symptoms, stop the infusion immediately and contact your doctor urgently. Pay particular attention if your doctor has detected inhibitors in your blood.
skin redness
skin rash
development of erythematous papules on the skin (urticaria)
widespread itching
swelling of the lips and tongue
breathing difficulty (dyspnoea)
difficulty inhaling and/or exhaling due to airway constriction (respiratory distress)
chest tightness
general feeling of malaise
dizziness
decrease in blood pressure
loss of consciousness
sudden swelling of the skin or mucous membranes, with or without difficulty swallowing or breathing (angioedema)
formation of blood clots in small blood vessels throughout the body (disseminated intravascular coagulation or DIC)
heart attack (myocardial infarction)
rapid heartbeat (tachycardia)
decrease in blood pressure (hypotension)
formation of blood clots (thromboembolic events)
blockage of a blood vessel by a blood clot (e.g. pulmonary embolism, venous thrombosis, arterial thrombosis, cerebral artery thrombosis)
facial flushing
difficulty inhaling and/or exhaling due to airway constriction (respiratory distress)
difficulty breathing (dyspnoea)
kidney disease with symptoms such as eyelid, facial and leg swelling, weight gain, and protein loss in urine (nephrotic syndrome). If your doctor has detected inhibitors in your blood, you may be at risk of developing a condition known as serum sickness. If you experience any of the following symptoms, stop the infusion immediately and contact your doctor urgently.
skin rash
itching
joint pain (arthralgia), especially in fingers and toes
fever
swollen lymph nodes (lymphadenopathy)
low blood pressure (hypotension)
abnormal enlargement of the spleen (splenomegaly)

Other side effects
Uncommon side effects (may affect up to 1 in 100 people)

throat irritation, sore throat and dry cough
skin rash and itching
fever (pyrexia)

Side effects with unknown frequency (frequency cannot be estimated from the available data)

headache
fatigue
tingling sensation (paraesthesia)
feeling of malaise (nausea)
vomiting
development of erythematous papules all over the skin (urticaria)
chills
hypersensitivity reactions
burning and irritation at the injection site
drowsiness
facial flushing
chest tightness

The following side effects have been observed with products in the same class:
Abnormal or reduced sensation (paraesthesia)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor. You can also report side effects directly via the national reporting system at: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store FIXNOVE

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and the carton. The expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C). Do not freeze.
Keep the vial in the outer packaging to protect the medicine from light.
Within the stated shelf life, FIXNOVE may be stored at room temperature up to 25°C for a maximum of 3 months. Record the start and end dates of room temperature storage (up to 25°C) on the product packaging. You must use FIXNOVE within these three months.
After this period, FIXNOVE must not be returned to the refrigerator, but must be used immediately or disposed of.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What FIXNOVE contains
Powder

The active substance is human coagulation factor IX. One vial of powder for injectable solution contains 600 IU of human coagulation factor IX. 1 ml of solution contains approximately 120 IU of human coagulation factor IX after reconstitution with 5 ml of sterile water for injection.
The other components are sodium chloride and sodium citrate.

Solvent

Sterile water for injection

Description of the appearance of FIXNOVE and contents of the pack
FIXNOVE is a white or pale yellow powder for preparing an injectable solution. After reconstitution with the solvent supplied in the pack (sterile water for injection), the solution appears clear or slightly opalescent. Do not use the product if particulate matter is present, or if there are changes in colour or turbidity.
Pack: 1 x 600 IU
Each pack contains: - 1 vial of FIXNOVE 600 IU

1 vial with 5 ml of sterile water for injection
1 transfer needle
1 venting needle
1 filter needle
1 disposable needle
1 disposable syringe (5 ml)
1 infusion set Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder
Baxalta Innovations GmbH
Industriestrasse 67, A – 1221 Vienna
Representative in Italy:
Takeda Italia S.p.A.
Tel. +39 06 502601
Manufacturer
Takeda Manufacturing Austria AG
Industriestrasse 67
1221 Vienna, Austria
Marketing Authorisation Number:
FIXNOVE 600 IU/5 ml A.I.C. n. 038324024
This medicinal product is authorised in the European Economic Area Member States under the
following names:
Austria, Bulgaria, Czech Republic, Estonia, Germany, Latvia, Lithuania, Norway, Poland,
Portugal, Romania, Slovakia, Slovenia, Spain, Sweden: Immunine
Italy: Fixnove
More detailed information on this medicinal product is available on the website of the Italian Medicines Agency (https://www.aifa.gov.it/).

The following information is intended exclusively for healthcare professionals:

Dosage and administration
Treatment must be initiated under the supervision of a physician experienced in the management of haemophilia.
Dosage
The dose and duration of replacement therapy depend on the severity of factor IX deficiency, the location and extent of bleeding, and the clinical condition of the patient.
The number of units of factor IX administered is expressed in International Units (IU), relative to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed as a percentage (relative to normal human plasma) or in International Units (relative to an international standard for factor IX concentrates in plasma).
One International Unit (IU) of factor IX activity is equivalent to the amount of factor IX present in 1 ml of normal human plasma.

On-demand treatment
The calculation of the required dose of factor IX is based on the empirical observation that 1 International Unit (IU) of factor IX per kg of body weight increases plasma factor IX activity by 1.1% of normal activity in patients aged 12 years and older.
The required dose is determined using the following formula:
Required units = body weight (kg) × desired increase in factor IX (%) (IU/dL) × 0.9
The amount to be administered and the frequency of administration should always be guided by clinical efficacy for each individual case. It is rarely necessary to administer factor IX products more than once daily.

In the event of the following bleeding episodes, factor IX activity should not fall below the specified plasma activity level (% of normal or IU/dL) during the corresponding period.
The following table may be used as a guide for dosing in bleeding episodes and surgical procedures:

Type of bleeding/ Plasma level of Dosing frequency (hours) / Duration of
Surgical procedure Factor IX required therapy (days)
(% of normal) (IU/dL)
Bleeding
Early haemarthrosis, 20–40 Repeat infusion every 24 hours for at least
intramuscular or oral 1 day until resolution of the bleeding episode,
bleeding. as indicated by pain, or until healing occurs.
More extensive haemarthroses, 30–60 Repeat infusion every 24 hours for 3–4
intramuscular bleeding, or days or longer, until pain and acute disability
haematomas. resolve.
Life-threatening bleeding 60–100 Repeat infusion every 8–24 hours until the
risk has been overcome.

Surgical procedures
Type of bleeding/ Plasma level of Dosing frequency (hours) / Duration of
Surgical procedure Factor IX required therapy (days)
(% of normal) (IU/dL)
Minor 30–60 Every 24 hours for at least 1 day, until
Including dental extractions healing is achieved.
Major surgery 80–100 Repeat infusion every 8–24 hours until
(pre- and post-operative adequate wound healing is achieved;
period) subsequently continue therapy for at least
7 additional days to maintain factor IX activity
between 30–60%.

Prophylaxis
For long-term prophylaxis of bleeding in patients with severe haemophilia B, doses of 20–40 IU of factor IX per kg body weight are usually administered every 3–4 days.
In some cases, particularly in younger patients, shorter intervals or higher doses may be required.
During treatment, it is recommended to perform appropriate monitoring of factor IX levels to determine the dose and frequency of infusions. In particular, during major surgical procedures, careful monitoring of replacement therapy using coagulation tests (plasma factor IX activity) is essential. Individual patient response to factor IX may vary, with different in vivo recovery levels and half-lives.

Paediatric population
Based on available clinical data, dosage recommendations can be provided for paediatric patients aged 12 to 18 years. For patients aged 6 to 12 years, available clinical data are insufficient to provide a dosage recommendation.

Undesirable effects
Special population
The use of FIXNOVE has been studied in paediatric patients with haemophilia B. The safety profile was similar to that observed in adults treated with FIXNOVE.
The use of FIXNOVE has been evaluated in two observational studies, one in children up to 6 years of age and another in patients aged 0 to 64 years with haemophilia B. The safety profile in children up to 6 years of age was similar to that in children over 6 years of age and in adults treated with FIXNOVE.

PATIENT LEAFLET: INFORMATION FOR THE USER

FIXNOVE 1200 IU

Powder and solvent for injectable solution or for infusion
human blood coagulation factor IX
Please read this leaflet carefully before using this medicine
because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, consult your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
If you experience any adverse reactions, including those not listed in this leaflet, consult your doctor or pharmacist. See section 4.

Contents of this leaflet:

What FIXNOVE is and what it is used for
What you need to know before using FIXNOVE
How to use FIXNOVE
Possible side effects
How to store FIXNOVE
Contents of the pack and other information

1. What FIXNOVE is and what it is used for

FIXNOVE is a coagulation factor IX concentrate. It replaces the missing or inadequately functioning factor IX in cases of haemophilia B. Haemophilia B is a hereditary, sex-linked blood coagulation disorder caused by reduced levels of factor IX, leading to severe bleeding into joints, muscles, or internal organs, either spontaneously or following accidental or surgical trauma.
Administration of FIXNOVE enables temporary correction of the factor IX deficiency and reduces the tendency to bleed.
FIXNOVE is used for the treatment and prophylaxis of bleeding episodes in patients with congenital haemophilia B.
FIXNOVE is indicated for all age groups starting from children over 6 years of age.
Available data are insufficient to recommend the use of FIXNOVE in children under 6 years of age.

2. What you should know before using FIXNOVE

Do not use FIXNOVE

if you are allergic to human coagulation factor IX or to any of the other ingredients of this medicine (listed in section 6), if you have a known allergic reaction to heparin, or if you have experienced an abnormal decrease in blood cells involved in clot formation following heparin administration ( heparin-induced thrombocytopenia ).

After appropriate treatment of these conditions, FIXNOVE should only be used in the case of
life-threatening bleeding episodes.
Warnings and precautions
Talk to your doctor or pharmacist before using FIXNOVE.
In case of allergic reactions:
There is a rare possibility of experiencing a severe and sudden allergic reaction (anaphylactic reaction)
to FIXNOVE.
If any of the following symptoms occur, stop the infusion immediately
and contact your doctor immediately . These symptoms may be early signs of anaphylactic shock and
require prompt emergency intervention.

skin flushing
skin rash
formation of erythematous skin papules (urticaria)
generalized itching
swelling of the lips and tongue
difficulty breathing (dyspnea)
difficulty inhaling/exhaling due to airway constriction (respiratory distress)
chest tightness
general feeling of malaise
dizziness
drop in blood pressure
loss of consciousness

When monitoring is required:

Your doctor will regularly perform blood tests to ensure that the current dose is adequate and that you are receiving sufficient factor IX.
To promptly detect possible complications, your doctor will monitor you closely, especially if you are receiving high doses of FIXNOVE or if you have a predisposition to thrombosis. In such cases, a lower level of factor IX, the active substance in FIXNOVE, may also be administered.

In case of persistent bleeding:

If your bleeding is not controlled with FIXNOVE, contact your doctor immediately . You may have developed factor IX inhibitors. Factor IX inhibitors are antibodies in the blood that counteract the activity of factor IX. This reduces the effectiveness of FIXNOVE in treating bleeding. Your doctor will perform the necessary tests to confirm this.
There may be a possible link between the development of factor IX inhibitors and allergic reactions. Patients with factor IX inhibitors may have an increased risk of severe and sudden allergic reactions (anaphylaxis). Therefore, patients who develop an allergic reaction should be tested for the presence of a factor IX inhibitor.

Inform your doctor if you have liver or heart disease or if you have recently undergone major surgery, as there is an increased risk of blood clotting complications.
Information on safety regarding transmissible agents
For medicines derived from human blood or plasma, several measures are taken to prevent the transmission of infections to patients. These measures include:

careful selection of blood and plasma donors to exclude individuals at risk of carrying infections,
testing of each donation and plasma pools for signs of viruses/infections,
inclusion of processing steps capable of inactivating or removing viruses during blood or plasma manufacturing.

Nevertheless, when administering medicinal products derived from human blood or plasma, it is not possible to completely exclude the risk of transmitting infections. This also applies to unknown or emerging viruses and other types of infections.
The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus, and against the non-enveloped hepatitis A virus.
The measures taken may have limited effectiveness against non-enveloped viruses such as parvovirus B19 [a virus causing skin redness (fifth disease)].
Parvovirus B19 infection can be serious for pregnant women (fetal infection) and for individuals with immunodeficiency or certain types of anemia (e.g., sickle cell anemia or hemolytic anemia).
Your doctor may recommend that you consider vaccination against hepatitis A and B if you are undergoing regular/repeated treatment with human plasma-derived products.
It is strongly recommended that, each time FIXNOVE is administered to you, the name and batch number of the medicine be recorded to maintain traceability of the batches used.
Children
Available data are insufficient to recommend the use of FIXNOVE in children under 6 years of age.
Other medicines and FIXNOVE
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
No interactions of FIXNOVE with other medicines are known.
Pregnancy and breastfeeding
Haemophilia B in women is very rare. Therefore, there is no experience regarding the use of FIXNOVE during pregnancy and breastfeeding.
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor before using this medicine. Your doctor will decide whether you can use FIXNOVE during pregnancy and breastfeeding.
Driving and using machines
No effects on the ability to drive vehicles or use machines have been observed.
FIXNOVE contains sodium chloride and sodium citrate
FIXNOVE 1200 IU contains 41 mg of sodium (main component of table salt) per vial. This corresponds to 2% of the maximum daily recommended dietary intake for an adult.

3. How to use FIXNOVE

Your treatment must be initiated and supervised by physicians experienced in the management of haemophilia B.
Your doctor will determine the appropriate dose for you, based on your individual requirements. If you feel that the effect of FIXNOVE is too strong or too weak, please consult your doctor.

Use in children
Available data are insufficient to recommend the use of FIXNOVE in children under 6 years of age.

Monitoring by your doctor
Your doctor will perform appropriate laboratory tests at regular intervals to ensure that adequate factor IX levels have been achieved. This is particularly important in the case of major surgical procedures or life-threatening bleeding episodes.

Patients who develop inhibitors
If the desired plasma level of factor IX is not achieved despite administration of an appropriate dose, or if bleeding does not stop, inhibitors may be present. Your doctor will check for the presence of inhibitors using appropriate tests. In case inhibitors develop, contact with a specialized haemophilia centre is required.
If you have developed factor IX inhibitors, you may require higher amounts of FIXNOVE to control bleeding. If this dose fails to control the bleeding, your doctor will consider alternative therapy. Do not increase the dose of FIXNOVE to control bleeding without first consulting your doctor.

Frequency of administration
Your doctor will explain the frequency and intervals of FIXNOVE administration, tailored to your individual needs and response to FIXNOVE.

Route and method of administration
FIXNOVE is administered slowly intravenously (by intravenous injection) after reconstitution with the solvent provided in the package.
FIXNOVE must not be mixed with other medicinal products prior to administration, as this may compromise the efficacy and safety of the product.
Follow your doctor’s instructions carefully.
The rate of administration depends on your comfort level and must not exceed 2 ml per minute.

Use only the administration set supplied in the package. If other sets are used, FIXNOVE may adhere to the inside of the infusion set, resulting in an incorrect dose being administered.
If you are also receiving other medicinal products through the same venous access, the line must be flushed with a suitable solution (e.g. saline solution) before and after administration of FIXNOVE.
Reconstitute FIXNOVE only immediately before use and administer the solution immediately. (The solution contains no preservatives.) The infusion must be completed within 3 hours after reconstitution.
The injection solution should be clear or slightly whitish (opalescent). Do not use solutions that appear cloudy or contain visible particles.
Any unused reconstituted product must be properly discarded.

Reconstitution of the lyophilisate to prepare an injection solution:
Ensure that you prepare the solution under the cleanest and most sterile conditions possible!

Bring the vial with intact rubber stopper containing the solvent (sterile water for injection) to room temperature (max. +37°C).
Remove the protective caps from the rubber stoppers of both the concentrate and solvent vials (Fig. A) and disinfect the rubber stoppers of both vials.
Remove the protective cap from one end of the transfer needle supplied in the package by twisting and pulling it off. Insert the exposed needle through the rubber stopper of the solvent vial (Fig. B and C).
Remove the protective cap from the other end of the transfer needle, taking care not to touch the exposed part.
Invert the solvent vial over the concentrate vial and insert the free end of the transfer needle through the rubber stopper of the concentrate vial (Fig. D). The solvent will be drawn into the concentrate vial by vacuum.
After all the solvent has been transferred into the concentrate vial, separate the two vials by removing the transfer needle from the concentrate vial (Fig. E). Gently swirl the concentrate vial to accelerate dissolution.
After complete reconstitution of the concentrate, insert the vent needle supplied in the package (Fig. F); any foam present will dissipate. Remove the vent needle.

Injection / Infusion:
Ensure that you prepare the solution under the cleanest and most sterile conditions possible!

Remove the protective cap from the filter needle supplied in the package by twisting and pulling it off, and attach the filter needle to the sterile disposable syringe. Draw the solution into the syringe (Fig. G).
Disconnect the filter needle from the syringe and slowly inject the solution intravenously (maximum injection rate 2 ml/min) using the infusion set supplied in the package (or the disposable needle supplied).

If administered by infusion, a single-use butterfly infusion set with an appropriate filter must be used.
Duration of treatment
Replacement therapy with FIXNOVE is generally a lifelong treatment.

If you use more FIXNOVE than you should
Contact your doctor. No symptoms related to factor IX overdose have been reported.

If you forget to use FIXNOVE

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

If you stop treatment with FIXNOVE
Do not stop treatment with FIXNOVE without first consulting your doctor.
If you have any questions about the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
If you experience any of the following serious side effects, contact your doctor immediately

severe allergic reaction (anaphylactic reaction). If you experience any of the following symptoms, stop the infusion immediately and contact your doctor urgently. Pay particular attention if your doctor has detected inhibitors in your blood.
skin redness
skin rash
development of erythematous papules on the skin (urticaria)
widespread itching
swelling of the lips and tongue
breathing difficulties (dyspnea)
difficulty inhaling and/or exhaling due to airway constriction (respiratory distress)
chest tightness
general feeling of malaise
dizziness
decrease in blood pressure
loss of consciousness
sudden swelling of the skin or mucous membranes, with or without difficulty swallowing or breathing (angioedema)
formation of blood clots in small blood vessels throughout the body (disseminated intravascular coagulation or DIC)
heart attack (myocardial infarction)
rapid heartbeat (tachycardia)
decrease in blood pressure (hypotension)
formation of blood clots (thromboembolic events)
blockage of a blood vessel by a blood clot (e.g. pulmonary embolism, venous thrombosis, arterial thrombosis, cerebral arterial thrombosis)
facial flushing
difficulty inhaling and/or exhaling due to airway constriction (respiratory distress)
difficulty breathing (dyspnea)
kidney disease with symptoms such as eyelid, facial and leg edema, weight gain, and protein loss in urine (nephrotic syndrome).

If your doctor has detected inhibitors in your blood, you may be at risk of developing a condition known as serum sickness. If you experience any of the following symptoms, stop the infusion immediately and contact your doctor urgently.

skin rash
itching
joint pain (arthralgia), especially in fingers and toes
fever
swollen lymph nodes (lymphadenopathy)
drop in blood pressure (hypotension)
abnormal enlargement of the spleen (splenomegaly)

Other side effects
Uncommon side effects (may affect up to 1 in 100 people)

throat irritation, sore throat and dry cough
skin rash and itching
fever (pyrexia)

Side effects with unknown frequency (frequency cannot be estimated from available data)

headache
fatigue
tingling sensation
feeling of discomfort (nausea)
vomiting
development of erythematous papules all over the body (urticaria)
chills
hypersensitivity reactions
burning and irritation at the injection site
drowsiness
facial flushing
chest tightness

The following side effects have been observed with products belonging to the same
group:
Abnormal or reduced sensation (paresthesia)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor. You may also report side effects directly via the national reporting system at: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store FIXNOVE

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and on the carton. The expiry date refers to the last day of that month.
Store in the refrigerator (2°C - 8°C). Do not freeze.
Keep the vial in the outer packaging to protect the medicine from light.
During the stated shelf life, FIXNOVE may be stored at room temperature up to 25°C for a maximum of 3 months. Record the start and end dates of room temperature storage (up to 25°C) on the product packaging. You must use FIXNOVE within these three months.
After this period, FIXNOVE must not be returned to the refrigerator, but must be used immediately or disposed of.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What FIXNOVE contains
Powder

The active substance is human coagulation factor IX. One vial of powder for injectable solution contains 1200 IU of human coagulation factor IX. 1 ml of solution contains approximately 120 IU of human coagulation factor IX after reconstitution with 10 ml of sterile water for injection.
The other components are sodium chloride and sodium citrate.

Solvent

Sterile water for injection

Description of the appearance of FIXNOVE and package contents
FIXNOVE is a white or slightly yellow powder for preparing an injectable solution. After
reconstitution with the solvent supplied in the pack (sterile water for injection),
the solution appears clear or slightly milky (opalescent). Do not use the product if particulate matter is present, or if there are changes in colour or turbidity.
Pack size: 1 x 1200 IU
Each pack contains: - 1 vial of FIXNOVE 1200 IU

1 vial containing 10 ml of sterile water for injection
1 transfer needle
1 venting needle
1 filter needle
1 single-use needle
1 single-use syringe (10 ml)
1 infusion set

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder
Baxalta Innovations GmbH
Industriestrasse 67, A – 1221 Vienna
Representative in Italy:
Takeda Italia S.p.A.
Tel. +39 06 502601

Manufacturer
Takeda Manufacturing Austria AG
Industriestrasse 67
1221 Vienna, Austria

Marketing Authorization Number:
FIXNOVE 1200 IU/10 ml A.I.C. No. 038324036

This medicinal product is authorized in the European Economic Area Member States under the following names:
Austria, Bulgaria, Czech Republic, Estonia, Germany, Latvia, Lithuania, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden: Immunine
Italy: Fixnove

More detailed information on this medicinal product is available on the website of the Italian Medicines Agency (https://www.aifa.gov.it/).

The following information is intended exclusively for healthcare professionals:

Posology and method of administration
Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia.
Dosage
The dose and duration of replacement therapy depend on the severity of factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition.
The number of units of factor IX administered is expressed in International Units (IU), relative to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed as a percentage (relative to normal human plasma) or in International Units (relative to an international standard for factor IX concentrates in plasma).
One International Unit (IU) of factor IX activity is equivalent to the amount of factor IX present in 1 ml of normal human plasma.

Treatment on demand
The calculation of the required dose of factor IX is based on empirical observations showing that 1 International Unit (IU) of factor IX per kg of body weight increases plasma factor IX activity by 1.1% of normal activity in patients aged 12 years and older.
The required dose can be determined using the following formula:
Required units = body weight (kg) × desired increase in factor IX (%) (IU/dl) × 0.9
The amount to be administered and the frequency of administration should always be guided by clinical efficacy in each individual case. It is rarely necessary to administer factor IX products more than once daily.

In the event of the following bleeding episodes, factor IX activity should not fall below the indicated plasma activity level (% of normal or IU/dl) during the corresponding period.
The following table may serve as a guide for dosing in cases of bleeding episodes and surgical procedures:

| Bleeding/Surgical procedure | Plasma level of Factor IX required (% of normal) (IU/dl) | Frequency of doses (hours) / Duration of therapy (days) | |-------------------------------|------------------------------------------------------------|----------------------------------------------------------| | Early haemarthrosis, intramuscular or oral bleeding | 20–40 | Repeat infusion every 24 hours for at least one day until the bleeding episode, as indicated by pain, is resolved or healing is achieved. | | More extensive haemarthroses, intramuscular bleeding or haematomas | 30–60 | Repeat infusion every 24 hours for 3–4 days or longer, until pain and acute disability have resolved. | | Life-threatening bleeding | 60–100 | Repeat infusion every 8–24 hours until the risk has passed. | | Surgical procedures | | | | Minor surgery, including dental extractions | 30–60 | Every 24 hours for at least 1 day, until healing is achieved. | | Major surgery (pre- and post-operative) | 80–100 | Repeat infusion every 8–24 hours until adequate wound healing is achieved; thereafter continue therapy for at least another 7 days to maintain factor IX activity between 30–60%. |

During treatment, appropriate monitoring of factor IX levels is recommended to determine the dose and frequency of infusions. Especially in the case of major surgery, careful monitoring of replacement therapy using coagulation tests (plasma factor IX activity) is essential. Individual patient response to factor IX may vary, with different levels of in vivo recovery and half-life.

Paediatric population
Based on available clinical data, dosing recommendations can be provided for paediatric patients aged between 12 and 18 years. For children aged between 6 and 12 years, available clinical data are insufficient to provide a dosing recommendation.

Undesirable effects
Special populations
The use of FIXNOVE has been studied in paediatric patients with haemophilia B. The safety profile was similar to that observed in adults treated with FIXNOVE.
The use of FIXNOVE has been evaluated in two observational studies, one in children up to 6 years of age and another in patients aged 0 to 64 years with haemophilia B. Safety in children up to 6 years of age was similar to that observed in children over 6 years of age and in adults treated with FIXNOVE.