Flebogamma DIF 100 mg/ml solution for infusion

What Flebogamma DIF is

Flebogamma DIF is one of the group of medicines called intravenous immunoglobulins. These are used to treat conditions where the body?s defence system against disease is not working properly.

What Flebogamma DIF is used for

Treatment of adults, children and adolescents (0-18 years) who do not have sufficient antibodies (replacement therapy) such as:

Patients with Primary Immunodeficiency Syndromes PID, an inborn lack of antibodies. Hypogammaglobulinaemia a condition implying low immunoglobulin levels in your blood and recurrent bacterial infections in patients with chronic lymphocytic leukaemia cancer of the blood where too many white blood cells are produced, in whom prophylactic antibiotics have failed. Hypogammaglobulinaemia a condition implying low immunoglobulin levels in your blood and recurrent bacterial infections in myeloma tumour composed of cells derived from the bone marrow patients who failed to respond to pneumococcal immunisation. Hypogammaglobulinaemia a condition implying low immunoglobulin levels in your blood in patients after a stem cell transplantation allogeneic haematopoietic stem cell transplantation, when you are given stem cells from another person.

Treatment of children and adolescents (0-18 years) who do not have sufficient antibodies (replacement therapy) in:

The Acquired Immune Deficiency Syndrome AIDS, it can be used to prevent troublesome infections.

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Treatment of adults, children and adolescents (0-18 years) with certain autoimmune disorders (immunomodulation). There are three groups:

Idiopathic Thrombocytopenic Purpura ITP, a condition where the number of platelets in the blood stream is greatly reduced. Platelets form an important part of the clotting process and a reduction in their numbers may cause unwanted bleeding and bruising. The product is also used in patients at high risk of bleeding or prior to surgery to correct the platelet count.

Guillain Barré syndrome, where the immune system damages the nerves and hinders them from working properly.

Kawasaki disease, an illness in children where the blood vessels arteries in the body become enlarged.

Do not use Flebogamma DIF

• If you are allergic (hypersensitive) to human normal immunoglobulin or any of the other ingredients of Flebogamma DIF (for a complete list of ingredients see section 6 of this leaflet).
• If you do not have enough immunoglobulins of the type IgA in your blood or have developed antibodies to IgA.
• If you have hereditary fructose intolerance, a quite rare genetic condition where the enzyme for breaking down fructose is not produced.

Take special care with Flebogamma DIF

Certain side effects may occur more frequently:
- in case of high rate of infusion
- if you have hypo- or agammaglobulinaemia (a condition implying low immunoglobulin levels in your blood) with or without IgA deficiency
- if you are having Flebogamma DIF for the first time, or it has been switched from an alternative human normal immunoglobulin (IVIg) product, or it is a long time since your last infusion (e.g. several weeks). You will be watched carefully until an hour after the infusion to detect potential side effects.

Allergic reactions are rare. It may happen particularly if you do not have enough immunoglobulins of the type IgA in your blood or have developed antibodies to IgA.

Rarely, human normal immunoglobulin can induce a fall in blood pressure with allergic reaction, even if you had tolerated previous treatment with human normal immunoglobulin.

Patients with pre-existing risk factors

Please tell your doctor if you have any other condition andor illness, as caution is required in patients with pre-existing risk factors for thrombotic events. In particular, tell your doctor if you have diabetes high blood pressure history of vascular disease or thrombosis overweight blood volume decrease diseases which increase blood viscosity

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advanced age

Patients with a kidney problem

If you have a kidney problem, your doctor should consider whether to stop treatment since cases of acute renal failure have been reported in patients receiving IVIg therapy, generally in patients with risk factors.

Tell your doctor, even when any of the above-mentioned circumstances had happened to you in the past.

Special safety warning

When medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. These include careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, and the testing of each donation and pools of plasma for signs of virus/infections. Manufacturers of these products also include steps in the processing of the blood or plasma that can inactivate or remove viruses. Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot be totally excluded. This applies to any unknown or emerging viruses or 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 the non-enveloped hepatitis A and parvovirus B19 viruses.

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

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Effects on vaccines Flebogamma DIF may reduce the effectiveness of certain type of vaccines live attenuated virus vaccines such as measles, rubella, mumps and varicella.

Effects on blood tests

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

Pregnancy and breast-feeding

If you are pregnant or breast-feeding you must tell your doctor. Your doctor will decide if Flebogamma DIF can be used during pregnancy and breast-feeding.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Dizziness can sometimes occur and might affect the ability to drive and use machines.

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Important information about some of the ingredients of Flebogamma DIF

This medicine contains 50 mg of sorbitol per ml. If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before taking this medicine.
In babies and young children hereditary fructose intolerance may not yet be diagnosed and may be fatal, thus, they should not receive this medicine.

Flebogamma DIF is given by injection into your veins (intravenous administration). It may be self administered if you have been fully trained by hospital staff. You must make up the infusion in exactly the way you have been shown in order to stop germs getting in. You must never self administer it alone; a responsible adult must be always present .

The dose that you will be given will depend on your illness and body weight and will be worked out by your doctor (please see section ?Instructions for healthcare professionals? given at the end of this leaflet).

At the beginning of your infusion you will receive Flebogamma DIF at a slow rate (0.01 ml/kg/min). Depending on how comfortable you feel, your doctor may then gradually increase the infusion rate (up to 0.08 ml/kg/min).

Use in children

The dose in children is not considered to be different to that of adults as it will be given depending on the illness and body weight of the children.

If you use more Flebogamma DIF than you should

If you get more Flebogamma DIF than you should, your body may take on too much fluid. This could particularly happen when you are a patient at risk, e.g. an elderly patient or a patient having problems with your kidneys. Tell your doctor immediately.

If you forget to use Flebogamma DIF

Tell your doctor or pharmacist immediately and follow his/her instructions.
You must not be given a double dose to make up for a forgotten dose.

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

In rare and isolated cases, the following side effects have been reported with immunoglobulin preparations. Tell your doctor if any of the following side effects happen during or after the infusion:
-A sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even if you have shown no hypersensitivity to previous administration.
-Cases of temporary meningitis (reversible aseptic meningitis).
-Cases of temporary reduction in the number of the red cells in the blood (reversible haemolytic anaemia/haemolysis).
-Cases of transient cutaneous reactions.
-Increase in serum creatinine level and/or acute renal failure.

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Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses.

Three clinical studies with Flebogamma DIF 100 mg/ml were conducted. In these studies different side effects have been observed. These side effects and frequency are detailed below using the following convention:

• very common (affects more than 1 user in 10)
• common (affects 1 to 10 users in 100)
• uncommon (affects 1 to 10 users in 1,000)
• rare (affects 1 to 10 users in 10,000)
• very rare (affects less than 1 user in 10,000)
• not known (frequency cannot be estimated from the available data)

Very common:
- headache

Common tachycardia acceleration of the heart activity hypotension low blood pressure nausea back pain myalgia muscle pain pain fever body temperature increased rigors cold shivering sensation

Uncommon influenza flu urinary infection red blood cells and white blood cells decreased anorexia lack of appetite dizziness motion sickness radicular syndrome neck or back pain and other symptoms such as numbness, tingling and weakness in the arms or legs syncope vasovagal temporary loss of consciousness tremorchills to tremble conjunctivitis inflammation of the conjuntiva of the eyes maculopathy illness of the macula, in the retina of the eyes photophobia excessive sensitivity to light ear pain vertigo blood pressure increased or decreased flushing to blush haematoma thrombosis postnasal drip excessive mucus sinus pain wheezing abdominal pain including abdominal pain upper and abdominal pain distension diarrhoea flatulence vomiting acne ecchymosis large skin hematoma erythema redness of the skin

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pruritus itching rash eruption of the skin arthralgia joint pain muscle spasms or muscle tightness neck pain pain in extremities chest discomfortchest pain feeling cold infusion related reaction and infusion site reaction including infusion site erythema and infusion site pain fatigue feeling jittery nervousness influenza like illness malaise oedema peripheral haemoglobin decreased heart rate increased

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Keep out of the reach and sight of children.

Do not use Flebogamma DIF after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month.

Do not store above 30 ºC. Do not freeze.

The solution should be clear or slightly opalescent. Do not use Flebogamma DIF if you notice that the solution is cloudy or has deposits.

Any unused product or waste material should be disposed of in accordance with local requirements. Medicines should not be disposed via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

What Flebogamma DIF contains

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

One vial of 50 ml contains: 5g of human normal immunoglobulin
One vial of 100 ml contains: 10 g of human normal immunoglobulin
One vial of 200 ml contains: 20 g of human normal immunoglobulin

and The percentage of IgG subclasses is approximately 66.6 IgG1, 27.9 IgG2, 3.0 IgG32.5 IgG4. It contains trace amounts of IgA lower than 100 microgramsml.

• The other ingredients are sorbitol and water for injections (see section 2 for further information about ingredients).
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What Flebogamma DIF looks like and contents of the pack

Flebogamma DIF is a solution for infusion. The solution is clear or slightly opalescent and colourless or pale yellow.

Flebogamma DIF is supplied as 5 g/50 ml, 10 g/100 ml and 20 g/200 ml.
Pack size of 1 vial.
Not all sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
08150 Barcelona - Spain

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

BelgiëBelgiqueBelgien Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona TélTel 34 93 571 01 00 LuxembourgLuxemburg Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona TélTel 34 93 571 01 00

Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Te. 34 93 571 01 00 Magyarország Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Tel. 34 93 571 01 00

eská republika Grifols S.R.O. itná 2 CZ-120 00 Praha 2 Tel 4202 2223 1415 Malta Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Tel 34 93 571 01 00

Danmark Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Tlf 34 93 571 01 00 Nederland Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Tel 34 93 571 01 00

Deutschland Grifols Deutschland GmbH Siemensstraße 32 D-63225 Langen Tel 49 6103 75020 Norge Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Tlf 34 93 571 01 00

Eesti Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Tel 34 93 571 01 00 Österreich Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Tel 34 93 571 01 00

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Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona 34 93 571 01 00 Polska Grifols Polska Sp. z o. o. UL. Nowogrodzka 68 PL-02-014 Warsaw Tel. 48 22 504 06 41

España Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Tel 34 93 571 01 00 Portugal Grifols Portugal, Lda. Rua de São Sebastião, n 2 Zona Industrial de Cabra Figa P-2635-448 Rio de Mouro Tel 351 219 255 200

România Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Tel 34 93 571 01 00 France Grifols France, SARL Parc Technologique Sainte Victoire Bâtiment 10, 1er étage F-13590 Meyreuil Tél 33 442 54 44 00

Ireland Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Tel 34 93 571 01 00 Slovenija Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Tel 34 93 571 01 00

Ísland Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Sími 34 93 571 01 00 Slovenská republika Grifols International, S.A. Trnavská cesta 50 821 02, Bratislava Tel 421 2 44 63 82 01

Italia Grifols Italia S.p.A. Via Carducci, 62 d I-56010 Ghezzano Pisa Tel 39 050 8755 113 SuomiFinland Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona PuhTel 34 93 571 01 00

Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona 34 93 571 01 00 Sverige Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Tel 34 93 571 01 00

Latvija Instituto Grifols, S.A. Can Guasch, 2 - Parets del Vallès E-08150, Barcelona Tel 34 93 571 01 00 United Kingdom Grifols UK Ltd. Byron House Cambridge Business Park Cambridge, CB4 0WZ Tel 44 01 223 395 700

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Lietuva
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00

This leaflet was last approved in

The following information is intended for medical or healthcare professionals only (see section 3 for further information):

Posology and method of administration

The dose and posology is dependent on the indication.

In replacement therapy the dose may need to be individualised for each patient dependent on the pharmacokinetic and clinical response. The following dosage regimens are given as a guideline.

The dose recommendations are summarised in the following table:

Indication Dose Frequency Replacement therapy in primary immunodeficiency - starting dose 0.4 - 0.8 gkg thereafter every 3 - 4 weeks to obtain IgG 0.2 - 0.8 gkg trough level of at least 4 - 6 gl 0.2 - 0.4 gkg Replacement therapy in secondary immunodeficiency every 3 - 4 weeks to obtain IgG trough level of at least 4 - 6 gl Children and adolescents with AIDS 0.2 - 0.4 gkg every 3 - 4 weeks 0.2 - 0.4 gkg every 3 - 4 weeks Hypogammaglobulinaemia 4 gl in patients after allogeneic haematopoietic stem cell transplantation Immunomodulation Idiopathic Thrombocytopenic Purpura 0.8 - 1 gkg or on day 1, possibly repeated once within 3 days 0.4 gkgd for 2 - 5 days Guillain Barré syndrome 0.4 gkgd for 5 days Kawasaki disease 1.6 - 2 gkg or in several doses for 2 - 5 days in association with acetylsalicylic acid 2 gkg in one dose in association with acetylsalicylic acid Paediatric population See above See above

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Flebogamma DIF should be infused intravenously at an initial rate of 0.01 ml/kg/min for the first thirty minutes. If tolerated, advance to 0.02 ml/kg/min for the second 30 minutes. Again, if tolerated, advance to 0.04 ml/kg/min for the third 30 minutes. If the patient tolerates the infusion well, additional increments of 0.02 ml/kg/min may be made at 30-minute intervals up to a maximum of 0.08 ml/kg/min.

It has been reported that the frequency of adverse reactions to IVIg increases with the infusion rate. Infusion rates during the initial infusions should be slow. If there are no adverse reactions, the infusion rate for subsequent infusions can be slowly increased to the maximum rate. For patients experiencing adverse reactions, it is advisable to reduce the infusion rate in subsequent infusions and limit the maximum rate to 0.04 ml/kg/min, or administer IVIg at a 5% concentration.

Paediatric population

As the dosage for each indication is given by body weight and adjusted to the clinical outcome of the above mentioned conditions, the dosage in children is not considered to be different to that of adults.

Incompatibilities

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

Special precautions

Sorbitol

Each ml of this medicinal product contains 50 mg of sorbitol. Patients with rare hereditary problems of fructose intolerance must not take this medicine.

In case of inadvertent application and suspicion of hereditary fructose intolerance the infusion has to be stopped immediately, normal glycaemia has to be re-established and organ function has to be stabilized by means of intensive care.

Interferences with determination of blood glucose levels are not expected.

Paediatric population

In babies and young children hereditary fructose intolerance may not yet be diagnosed and may be fatal, thus, they should not receive this medicinal product.

It is strongly recommended that every time Flebogamma DIF is administered, the name and batch number of the product is recorded in order to maintain a record of the batches used.

Instructions for handling and disposal

The product should be brought at room temperature (no more than 30 ºC) before use.

The solution should be clear or slightly opalescent. Do not use Flebogamma DIF if you notice that the solution is cloudy or has deposits.

Any unused product or waste material should be disposed of in accordance with local requirements.

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