FLEBOGAMMA DIF 100 mg/ml SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Flebogamma DIF 100mg/ml solution for infusion

Normal human 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 signs of illness are the same as yours.
• If you get 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 package leaflet:

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

What is Flebogamma DIF

Flebogamma DIF contains normal human immunoglobulin, a highly purified protein extracted from human plasma (a part of the blood of 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 is Flebogamma DIF 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 duplicate the antibody title 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) of 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 progressive asymmetric 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 in which the enzyme responsible for breaking down fructose is not produced. 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 have had a long period of time (e.g., several weeks) 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
• decreased blood volume
• diseases that increase blood viscosity
• over 65 years of age

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 medication.

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 infection,

• 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 totally 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 be kept of the name of the medicine and the batch number administered (indicated on the label and box after Batch) in order 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 chickenpox, 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.

• The concomitant use of 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 should 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 (the main component of table/cooking 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 package leaflet).

At the start of the infusion, you will receive Flebogamma DIF at a low rate (0.01 ml/kg/min). If you tolerate it well, your doctor may gradually increase the infusion rate (up to 0.08 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 suffer from 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, coughing, 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 reactions on the skin).
• Increased serum creatinine levels (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 decreased blood pressure.

Other side effects:

Very common (may affect more than 1 infusion in 10):

• headache

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

• tachycardia (increased heart rate)
• hypotension (decreased blood pressure)
• fever (increased body temperature)
• chills (feeling of cold)
• nausea
• vomiting
• back pain
• myalgia (muscle pain)

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

• hypersensitivity
• cold (flu)
• dizziness
• tremors
• photophobia (excessive sensitivity to light)
• vertigo
• hypertension (increased blood pressure)
• wheezing
• abdominal pain (including upper abdominal pain)
• diarrhea
• flatulence
• pruritus
• skin rash
• limb discomfort
• muscle spasms and stiffness
• neck pain
• limb pain
• chest discomfort/chest pain
• fatigue
• feeling of cold
• discomfort
• peripheral edema
• increased heart rate
• bruising
• urinary tract infection
• aseptic meningitis
• decrease in red and white blood cells
• anorexia (loss of appetite)
• insomnia
• radicular syndrome (pain in the neck or back and other symptoms such as numbness, tingling, and weakness in arms and legs)
• vasovagal syncope (temporary loss of consciousness)
• conjunctivitis (inflammation of the conjunctiva of the eyes)
• maculopathy (disease of the macula, in the retina of the eyes)
• blurred vision
• ear pain
• cyanosis (bluish discoloration of the skin)
• increased or decreased blood pressure
• flushing
• hematoma
• thrombosis
• lymphedema
• dyspnea (difficulty breathing)
• epistaxis (nosebleed)
• runny nose (excess mucus)
• nasal pain
• upper respiratory tract syndrome
• abdominal discomfort and distension
• dry mouth
• hematemesis (vomiting blood)
• acne
• alopecia
• hyperhidrosis (excessive sweating)
• ecchymosis (bruising of the skin)
• erythema (redness of the skin)
• arthralgia (joint pain)
• musculoskeletal discomfort
• injection site reaction and reaction at the injection site (including erythema and pain at the infusion site)
• nervousness
• pseudogripal syndrome
• general physical deterioration
• decrease in hemoglobin
• increase in reticulocyte count
• decrease in heart rate

Other side effects in children and adolescents

It was observed that the proportion of headache, chills, fever, nausea, vomiting, decreased blood pressure, increased heart rate, and back pain was higher in children than in adults. Cyanosis (lack of oxygen in the blood) was reported in a child, but not in adults.

Side effects may decrease if Flebogamma DIF 50 mg/ml is administered instead of Flebogamma DIF 100 mg/ml. Consult your doctor if side effects increase.

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 Contents and Additional Information

Composition ofFlebogamma DIF

• The active ingredient is normal human immunoglobulin (IgIV). One ml contains 100 mg of normal human immunoglobulin, of which at least 97% is IgG.

Each 50 ml vial contains: 5 g of normal human immunoglobulin

Each 100 ml vial contains: 10 g of normal human immunoglobulin

Each 200 ml vial contains: 20 g of normal human immunoglobulin

The percentage of IgG subclasses is approximately 66.6% IgG1, 27.9% IgG2, 3.0% IgG3, and 2.5% IgG4. The IgA content is less than 100 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 Contents

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

Flebogamma DIF is presented in vials of 5 g/50 ml, 10 g/100 ml, and 20 g/200 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 more information on this medicinal product, please contact the local representative of the marketing authorization holder:

Date of Last Revision of thisLeaflet: 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 based on 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 ml/kg/min for the first 30 minutes. If well tolerated, increase the rate to 0.02 ml/kg/min for the next 30 minutes. Again, if well tolerated, increase the rate to 0.04 ml/kg/min for the next 30 minutes. If the patient tolerates the administration well, the rate can be further increased by 0.02 ml/kg/min at 30-minute intervals, up to a maximum of 0.08 ml/kg/min.

It has been shown that the frequency of adverse reactions to IgIV increases with the infusion rate. The infusion rate should be slow in initial administrations. If no adverse reactions occur, the rate for subsequent infusions can be gradually increased to reach the maximum rate. For patients who have experienced adverse reactions, it is recommended to reduce the infusion rate in subsequent infusions, limiting the maximum rate to 0.04 ml/kg/min or administering IgIV at a concentration of 5%.

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 medicinal product 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 may be potentially fatal and should be contraindicated in this population unless there is an absolute clinical need and no alternative is available.

Before receiving this medicinal product, the patient's medical history should be carefully 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 medicinal product 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 product and all materials that have come into contact with it should be carried out in accordance with local regulations.