FLEBOGAMMA DIF 50 mg/ml SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Flebogamma DIF50mg/ml solution for infusion

Human normal immunoglobulin (IgIV)

Read all of this leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack:

1. What Flebogamma DIF is and what it is used for
2. What you need to know before you use Flebogamma DIF
3. How to use Flebogamma DIF
4. Possible side effects
5. Storage of Flebogamma DIF
6. Contents of the pack and other information

1. What Flebogamma DIF is and what it is used for

What Flebogamma DIF is

Flebogamma DIF contains human normal immunoglobulin, a highly purified protein extracted from human plasma (a part of the blood from donors). This medicine belongs to a class of medicines called intravenous immunoglobulins. These are used to treat conditions in which the immune system does not function correctly against diseases.

What Flebogamma DIF is used for

Treatment in adults, children, and adolescents (2-18 years) who lack sufficient antibodies (Flebogamma DIF is used in replacement therapy). There are two groups:

• Patients with Primary Immunodeficiency Syndrome (PIS), a congenital deficiency of antibodies (group 1).

• Patients with Secondary Immunodeficiency Syndrome (SIS) in patients who suffer from severe or recurrent infections, who do not respond to antimicrobial treatment and who have demonstrated a deficiency of specific antibodies (PSAF)*or a serum level of <4 g/l (group 2).

*PSAF = inability to double the antibody titre against the pneumococcal polysaccharide and polymeric vaccine antigens.

Treatment of adults, children, and adolescents (2 – 18 years) who are susceptible and in whom active vaccination against measles is contraindicated or not recommended.

Treatment in adults, children, and adolescents (2-18 years) with certain autoimmune conditions (immunomodulation). These are classified into five groups:

• Primary immune thrombocytopenia, when the number of platelets in the bloodstream is drastically reduced. Platelets are an important part in the coagulation process, and a reduced number of platelets can cause bleeding and bruising. This product is also used in patients with a high risk of bleeding or before surgery, to increase the number of platelets.

• Guillain-Barré Syndrome, in which the immune system attacks the nerves and prevents them from functioning correctly.

• Kawasaki disease (in this case, together with acetylsalicylic acid), a childhood disease in which the blood vessels (arteries) in the body become enlarged.

• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a rare and progressive disease that causes weakness in the limbs, numbness, pain, and fatigue.

• Multifocal motor neuropathy (MMN), a rare disease that causes slow, asymmetric progressive weakness in the limbs without sensory loss.

2. What you need to know before you use Flebogamma DIF

Do not use Flebogamma DIF

• If you are allergic to human immunoglobulins or to any other component of this medicine (included in section 6).

• If you have IgA deficiency in blood or have developed antibodies to IgA.

• If you have fructose intolerance, a rare genetic disease that consists of the inability to produce the enzyme responsible for breaking down fructose. In infants and young children (0-2 years), hereditary fructose intolerance (HFI) may not have been diagnosed and could be fatal, so they should not receive this medicine. (See special precautions regarding excipients at the end of this section).

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use Flebogamma DIF.

Some adverse reactions may occur more frequently:

• if administered at a high infusion rate.
• if you receive Flebogamma DIF for the first time, or have changed from another human normal immunoglobulin (IgIV) product, or a long period of time (e.g., several weeks) has elapsed since the last infusion. You will be closely monitored for up to one hour after the infusion to detect possible adverse reactions.

Allergic reactions are rare. These may occur in isolated cases if you do not have sufficient IgA immunoglobulins in your blood or if you have developed anti-IgA antibodies.

Patients with pre-existing risk factors

Please inform your doctor if you have any other medical condition and/or disease, as closer monitoring is required in patients with pre-existing risk factors for thrombotic events (blood clot formation). In particular, inform your doctor if you have:

• diabetes
• high blood pressure
• history of vascular disease or thrombotic events
• overweight
• reduced blood volume
• diseases that increase blood viscosity
• aged over 65 years

Patients with kidney problems

If you have kidney disease and receive Flebogamma DIF for the first time, you may experience kidney problems.

Your doctor will consider the existing risk factors in your case and take appropriate measures, such as reducing the infusion rate or stopping treatment.

Effects on blood tests

After receiving Flebogamma DIF, the results of certain blood tests (serological tests) may be altered for some time. If you have a blood test after receiving Flebogamma DIF, please inform the analyst or your doctor that you have received this medicine.

Special safety precautions

When medicines are prepared from human blood or plasma, a series of measures must be taken to prevent the possible transmission of infections to patients. These measures include:

• careful selection of blood and plasma donors to ensure the exclusion of donors at risk of having infections,

• analysis of each donation and plasma pool to detect possible viruses or infections,

• inclusion of a series of stages in the processing of blood or plasma that can inactivate or eliminate viruses.

Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of transmitting infections cannot be completely excluded. This also applies to unknown or emerging viruses and other types of infections.

The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus, and for non-enveloped viruses such as hepatitis A virus and parvovirus B19.

Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections, possibly because the antibodies against these infections, such as those contained in the medicine, are protective.

It is highly recommended that each time Flebogamma DIF is administered to a patient, a record is kept of the name of the medicine and the batch number administered (indicated on the label and box after Batch) to maintain a relationship between the patient and the product batch.

Children and adolescents

Vital signs (body temperature, blood pressure, heart rate, and respiratory rate) should be monitored during the infusion of Flebogamma DIF.

Using Flebogamma DIF with other medicines

• Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

• Effects on vaccines: Flebogamma DIF may reduce the effectiveness of certain types of vaccines (live attenuated vaccines). In the case of rubella, mumps, and varicella, a period of up to 3 months should elapse after receiving this medicine and before receiving these vaccines. In the case of measles, the period is up to 1 year.

• Concomitant use with medicines that increase water excretion from the body (loop diuretics) should be avoided during treatment with Flebogamma DIF.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Patients may experience reactions (such as dizziness or nausea) during treatment that could affect their ability to drive and use machines.

Flebogamma DIF contains sorbitol

Sorbitol is a source of fructose. If you (or your child) have hereditary fructose intolerance (HFI), a rare genetic disease, you must not receive this medicine. Patients with HFI cannot break down fructose, which can cause serious adverse effects.

Consult your doctor before receiving this medicine if you (or your child) have HFI or if your child cannot take sweet foods or drinks because they cause dizziness, vomiting, or unpleasant effects such as bloating, stomach cramps, or diarrhea.

Flebogamma DIF contains sodium

This medicine contains less than 7.35 mg of sodium (main component of cooking/table salt) per 100 ml. This is equivalent to 0.37% of the maximum daily intake of 2 g of sodium recommended for an adult.

3. How to use Flebogamma DIF

Flebogamma DIF is for intravenous administration (injection into a vein). You can administer it yourself if you have previously received complete training from hospital staff or a healthcare professional. You must perform the infusion exactly as you have been taught to avoid the presence of germs. You should never administer an injection if you are alone; a healthcare professional with experience in preparing medicines, cannulation, administration, and monitoring of adverse reactions should always be present.

The dose you receive will depend on your disease and weight and will be calculated by your doctor (see section "Instructions for healthcare professionals" at the end of the leaflet).

At the start of the infusion, you will receive Flebogamma DIF at a low rate (0.01-0.02 ml/kg/min). If you tolerate it well, your doctor may gradually increase the infusion rate (up to 0.1 ml/kg/min).

Use in children over 2 years

The dose in children is not considered to be different from that in adults, as it depends on the disease and the child's weight.

If you receive more Flebogamma DIF than you should

If you receive more Flebogamma DIF than you should, your body may experience fluid overload. This can occur especially if you are a high-risk patient, for example, if you are elderly or have heart or kidney problems. Consult your doctor immediately.

If you forget to use Flebogamma DIF

Consult your doctor or pharmacist immediately and follow their instructions.

You should not administer a double dose to make up for a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

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

In some isolated cases, the following adverse reactions have been described with immunoglobulin preparations. Seek medical help immediately if you experience any of the following adverse reactions during or after the infusion:

• Sudden drop in blood pressure and, in isolated cases, anaphylactic shock (whose signs are skin rash, hypotension, palpitations, wheezing, cough, sneezing, and difficulty breathing, among others), even in patients who have not presented hypersensitivity to previous administrations.
• Cases of temporary non-infectious meningitis (whose signs are headache, fear or sensitivity to light, neck stiffness).
• Cases of temporary reduction in the number of red blood cells in the blood (reversible hemolytic anemia/hemolysis).
• Cases of transient skin reactions (adverse effects on the skin).
• Increased levels of serum creatinine (test that measures kidney function) and/or acute kidney failure (whose signs are pain in the lumbar area, fatigue, decreased urine output).
• Thromboembolic reactions such as myocardial infarction (pressure in the chest area with a feeling of a rapid heartbeat), stroke (weakness in the muscles of the face, arms, or legs, difficulty speaking or understanding others when they speak), pulmonary embolism (shortness of breath, chest pain, and fatigue), and deep vein thrombosis (pain and swelling in a limb).
• Cases of acute lung injury caused by transfusion (TRALI) that causes hypoxia (lack of oxygen), dyspnea (difficulty breathing), tachypnea (agitated breathing), cyanosis (lack of oxygen in the blood), fever, and hypotension.

Other side effects:

Common (may affect up to 1 in 10 infusions):

• headache
• fever (increase in body temperature)
• tachycardia (increase in heart rate)
• hypotension

Uncommon (may affect up to 1 in 100 infusions):

• bronchitis
• nasopharyngitis
• dizziness
• hypertension
• increased blood pressure
• wheezing
• productive cough
• abdominal pain (including upper abdominal pain)
• diarrhea
• vomiting
• nausea
• urticaria
• pruritus (itching)
• skin rash
• back pain
• myalgia (muscle pain)
• arthralgia (joint pain)
• rigidity (feeling of chills)
• pain
• reaction at the injection site
• positive Coombs test
• decrease in blood pressure

Rare (may affect up to 1 in 1,000 infusions):

• hypersensitivity
• abnormal behavior
• migraine
• fluctuations in blood pressure
• erythema (redness of the skin)
• cough
• asthma
• dyspnea (difficulty breathing)
• epistaxis (nosebleed)
• nasal discomfort
• throat pain
• contact dermatitis
• hyperhidrosis (excessive sweating)
• skin rash
• muscle spasms
• neck pain
• limb pain
• urinary retention
• weakness (fatigue)
• chest pain
• reaction at the infusion site (including redness of the skin, extravasation, swelling, and pain)
• reaction at the injection site (including swelling at the injection site, pain, itching, and swelling)
• peripheral edema
• increased alanine aminotransferase (liver transaminase)

Other side effects in children and adolescents

It was observed that the proportion of headache, fever, increased heart rate, and decreased blood pressure was higher in children than in adults.

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the national reporting system included in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Flebogamma DIF

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after EXP.

Do not store above 30°C. Do not freeze.

The solution should be clear or slightly opalescent. Do not use this medicine if the solution is cloudy or has deposits.

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 protect the environment.

6. Container Content and Additional Information

Composition ofFlebogamma DIF

• The active ingredient is normal human immunoglobulin (IgIV). One ml contains 50 mg of normal human immunoglobulin, of which at least 97% is IgG.

Each 10 ml vial contains: 0.5 g of normal human immunoglobulin

Each 50 ml vial contains: 2.5 g of normal human immunoglobulin

Each 100 ml vial contains: 5 g of normal human immunoglobulin

Each 200 ml vial contains: 10 g of normal human immunoglobulin

Each 400 ml vial contains: 20 g of normal human immunoglobulin

The percentage of IgG subclasses is approximately 66.6% IgG1, 28.5% IgG2, 2.7% IgG3, and 2.2% IgG4. The IgA content is less than 50 micrograms/ml.

• The remaining components are sorbitol and water for injectable preparations (see section 2 for more information on components).

Appearance of the Product and Container Content

Flebogamma DIF is an infusion solution. The solution is transparent or slightly opalescent, colorless or pale yellow.

Flebogamma DIF is presented in vials of 0.5 g/10 ml, 2.5 g/50 ml, 5 g/100 ml, 10 g/200 ml, and 20 g/400 ml.

Container size: 1 vial

Only some container sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Instituto Grifols, S.A.

Can Guasc, 2 - Parets del Vallès

08150 Barcelona - Spain

For further information on this medicinal product, please contact the local representative of the marketing authorization holder:

Date of Last Revision of this Leaflet: MM/YYYY

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu.

This information is intended only for healthcare professionals (see section 3 for more information):

Posology and Method of Administration

The dose and dosing regimen depend on the indication.

It may be necessary to individualize the dosing regimen for each patient according to the clinical response. The dose based on body weight may require adjustment in patients with low weight or overweight. The following dosing regimen can be used as a guideline.

The recommended posology is described in the following table:

Flebogamma DIF should be administered intravenously at an initial rate of 0.01-0.02 ml/kg/min during the first thirty minutes. If well tolerated, the administration rate can be gradually increased up to a maximum of 0.1 ml/kg/min.

In the clinical trial conducted with patients with chronic ITP, a significant increase in mean platelet levels (64,000/µl) was obtained, although without reaching normal levels.

Pediatric Population

Since the posology for each indication is based on body weight and adjusted according to the clinical outcome of the conditions indicated above, the posology in children does not differ from that indicated for adults.

Incompatibilities

Flebogamma DIF should not be mixed with other medicines or intravenous solutions and should be administered using a separate intravenous line.

Special Precautions

Sorbitol

Patients with hereditary fructose intolerance (HFI) should not receive this medicine unless it is strictly necessary.

Infants and children (under 2 years) may not be diagnosed with hereditary fructose intolerance (HFI). Medicines (containing sorbitol/fructose) administered intravenously can be potentially fatal and should be contraindicated for this population unless there is an absolute clinical need and no alternative is available.

Before receiving this medicine, the patient's medical history should be thoroughly reviewed for symptoms of HFI.

It is highly recommended that each time Flebogamma DIF is administered to a patient, a record is kept of the name of the medicine and the batch number administered in order to maintain a relationship between the patient and the batch of the product.

Handling and Disposal Instructions

The product should reach room temperature (not above 30 °C) before use.

The solution should be transparent or slightly opalescent. Do not use Flebogamma DIF if the solution is turbid or contains sediment.

Disposal of unused medicinal products and all materials that have come into contact with them should be carried out in accordance with local regulations.