Flebogamma DIF

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



 
 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Flebogamma DIF 50 mg/ml solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Human normal immunoglobulin (IVIg) 
 
One ml contains:   
Human normal immunoglobulin ……….. 50 mg  
(purity of at least 97% of IgG) 
 
Each vial of 10 ml contains: 0.5 g of human normal immunoglobulin 
Each vial of 50 ml contains: 2.5 g of human normal immunoglobulin 
Each vial of 100 ml contains: 5 g of human normal immunoglobulin 
Each vial of 200 ml contains: 10 g of human normal immunoglobulin 
Each vial of 400 ml contains: 20 g of human normal immunoglobulin 
 
Distribution of the IgG subclasses (approx. values): 
IgG1 66.6% 
IgG2 28.5% 
IgG3 2.7% 
IgG4 2.2% 
 
The maximum IgA content is 50 micrograms/ml. 
 
Produced from the plasma of human donors. 
 
Excipient with known effect: 
 
One ml contains 50 mg of D-sorbitol. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for infusion. 
 
The solution is clear or slightly opalescent and colourless or pale yellow. 
 
Flebogamma DIF is isotonic, with an osmolality from 240 to 370 mOsm/kg. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Replacement therapy in adults, children and adolescents (2 - 18 years) in: 
 
- Primary immunodeficiency syndromes (PID) with impaired antibody production 



 
 
 

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- Secondary immunodeficiencies (SID) in patients who suffer from severe or recurrent infections, 
ineffective antimicrobial treatment and either proven specific antibody failure (PSAF)* or 
serum IgG level of <4 g/l  

 
*PSAF= failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide 
and polypeptide antigen vaccines 
 
Immunomodulation in adults, children and adolescents (2 - 18 years) in: 
 
- Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery 

to correct the platelet count 
 
- Guillain Barré syndrome 
 
- Kawasaki disease (in conjunction with acetylsalicylic acid; see 4.2) 

 
- Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) 

 
- Multifocal motor neuropathy (MMN) 
 
4.2 Posology and method of administration 
 
Replacement therapy should be initiated and monitored under the supervision of a physician 
experienced in the treatment of immunodeficiency. 
 
Posology 
 
The dose and dose regimen is dependent on the indication. 
 
The dose may need to be individualised for each patient dependent on the clinical response. Dose 
based on body weight may require adjustment in underweight or overweight patients. The following 
dose regimens are given as a guideline. 
 
Replacement therapy in primary immunodeficiency syndromes 
 
The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 
6 g/l or within the normal reference range for the population age. Three to six months are required 
after the initiation of therapy for equilibration (steady-state IgG levels) to occur. The recommended 
starting dose is 0.4 - 0.8 g/kg given once followed by at least 0.2 g/kg given every three to four weeks. 
 
The dose required to achieve a trough level of IgG of 6 g/l is of the order of 0.2 - 0.8 g/kg/month. The 
dose interval when steady state has been reached varies from 3 - 4 weeks. 
 
IgG trough levels should be measured and assessed in conjunction with the incidence of infection. To 
reduce the rate of bacterial infections, it may be necessary to increase the dosage and aim for higher 
trough levels. 
 
Secondary immunodeficiencies (as defined in 4.1) 
 
The recommended dose is 0.2 - 0.4 g/kg every three to four weeks. 
 
IgG trough levels should be measured and assessed in conjunction with the incidence of infection. 
Dose should be adjusted as necessary to achieve optimal protection against infections, an increase 



 
 
 

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may be necessary in patients with persisting infection; a dose decrease can be considered when the 
patient remains infection free. 
 
Primary immune thrombocytopenia 
 
There are two alternative treatment schedules: 
• 0.8 - 1 g/kg given on day one; this dose may be repeated once within 3 days. 
• 0.4 g/kg given daily for two to five days.  
 
The treatment can be repeated if relapse occurs. 
 
Guillain Barré syndrome 
 
0.4 g/kg/day over 5 days (possible repeat of dosing in case of relapse). 
 
Kawasaki disease 
 
2.0 g/kg should be administered as a single dose. Patients should receive concomitant treatment with 
acetylsalicylic acid. 
 
Chronic inflammatory demyelinating polyneuropathy (CIDP) 
 
Starting dose: 2 g/kg divided over 2 - 5 consecutive days. 
Maintenance doses: 1 g/kg over 1 - 2 consecutive days every 3 weeks. 
The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 
6 months, the treatment should be discontinued. 
If the treatment is effective long term treatment should be subject to the physicians discretion based 
upon the patient response and maintenance response. The dosing and intervals may have to be adapted 
according to the individual course of the disease. 
 
Multifocal motor neuropathy (MMN) 
 
Starting dose: 2 g/kg divided over 2 - 5 consecutive days. 
Maintenance dose: 1 g/kg every 2 to 4 weeks or 2 g/kg every 4 to 8 weeks. 
The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 
6 months, the treatment should be discontinued. 
If the treatment is effective long term treatment should be subject to the physicians discretion based 
upon the patient response and maintenance response. The dosing and intervals may have to be adapted 
according to the individual course of the disease. 
 
The dose recommendations are summarised in the following table: 

 
Indication Dose Frequency of injections 

Replacement therapy:   
Primary immunodeficiency syndromes 
 
 
 
 
 

Starting dose: 
0.4 - 0.8 g/kg 
 
Maintenance 
dose: 
0.2 - 0.8 g/kg 

 
 
 
 
 
every 3 - 4 weeks  

Secondary immunodeficiencies (as defined 
in 4.1) 

0.2 - 0.4 g/kg 
 

every 3 - 4 weeks  
 



 
 
 

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Immunomodulation:   
Primary immune thrombocytopenia  
 
 
 
 

0.8 - 1 g/kg 
 
or 

 
0.4 g/kg/d 

on day 1, possibly repeated once 
within 3 days 
 
 
for 2 - 5 days 

Guillain Barré syndrome 0.4 g/kg/d for 5 days 
Kawasaki disease 2 g/kg in one dose in association with 

acetylsalicylic acid 
Chronic inflammatory demyelinating 
polyradiculoneuropathy (CIDP) 

Starting dose: 
2 g/kg 
 
Maintenance dose: 
1 g/kg 

 
in divided doses over 2 - 5 days 
 
 
every 3 weeks over 1 - 2 days 

Multifocal motor neuropathy (MMN) Starting dose: 
2 g/kg 
 
 
Maintenance dose: 
1 g/kg 
 
or 
 
2 g/kg 

 
in divided doses over 
2 - 5 consecutive days 
 
 
every 2 - 4 weeks 
 
 
 
every 4 - 8 weeks in divided doses 
over 2 - 5 days 

 
Paediatric population 
 
Flebogamma DIF 50 mg/ml is contraindicated in children aged 0 to 2 years (see section 4.3). 
 
The posology in children and adolescents (2 - 18 years) is not different to that of adults as the 
posology for each indication is given by body weight and adjusted to the clinical outcome of the 
above mentioned conditions. 
 
Hepatic impairment 
No evidence is available to require a dose adjustment. 
  
Renal impairment 
No dose adjustment unless clinically warranted, see section  4.4. 
 
Elderly 
No dose adjustment unless clinically warranted, see section 4.4. 
 
Method of administration 
 
For intravenous use. 
Flebogamma DIF 50 mg/ml should be infused intravenously at an initial rate of 
0.01 - 0.02 ml/kg/min for the first thirty minutes. See section 4.4. In case of adverse reaction, either 
the rate of administration must be reduced or the infusion stopped. If well tolerated, the rate of 
administration may gradually be increased to a maximum of 0.1 ml/kg/min.  
 



 
 
 

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4.3 Contraindications 
 
Hypersensitivity to the active substance (human immunoglobulins) or to any of the excipients (see 
sections 4.4 and 6.1). 
 
Fructose intolerance (see section 4.4).  
In babies and young children (aged 0 - 2 years) hereditary fructose intolerance (HFI) may not yet be 
diagnosed and may be fatal, thus, they must not receive this medicinal product. 
 
Patients with selective IgA deficiency who developed antibodies to IgA, as administering an 
IgA-containing product can result in anaphylaxis. 
 
4.4 Special warnings and precautions for use 
 
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 persons more than 2 years old with HFI, a spontaneous aversion for fructose-containing 
foods develops and may be combined with the onset of symptoms (vomiting, gastro-intestinal 
disorders, apathy, height and weight retardation). Therefore a detailed history with regard to 
HFI symptoms has to be taken of each patient prior to receiving Flebogamma DIF.  
In case of inadvertent administration and suspicion of 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. 
 
Traceability 
In order to improve the traceability of biological medicinal products, the name and the batch 
number of the administered product should be clearly recorded. 
 
Precautions for use 
Potential complications can often be avoided by ensuring that patients: 
- are not sensitive to human normal immunoglobulin by initially injecting the product slowly (at 

an initial rate of 0.01 - 0.02 ml/kg/min) 
- are carefully monitored for any symptoms throughout the infusion period. In particular, patients 

naive to human normal immunoglobulin, patients switched from an alternative IVIg product or 
when there has been a long interval since the previous infusion should be monitored at the 
hospital during the first infusion and for the first hour after the first infusion, in order to detect 
potential adverse signs. All other patients should be observed for at least 20 minutes after 
administration 

 
In all patients, IVIg administration requires: 
- adequate hydration prior to the initiation of the infusion of IVIg 
- monitoring of urine output 
- monitoring of serum creatinine levels 
- avoidance of concomitant use of loop diuretics (see 4.5) 
 
In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped.  
The treatment required depends on the nature and severity of the adverse reaction. 
 



 
 
 

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Infusion reaction 
 
Certain adverse reactions (e.g. headache, flushing, chills, myalgia, wheezing, tachycardia, lower back 
pain, nausea, and hypotension) may be related to the rate of infusion. The recommended infusion rate 
given under section 4.2 must be closely followed. Patients must be closely monitored and carefully 
observed for any symptoms throughout the infusion period. 
 
Adverse reactions may occur more frequently 
- in patients who receive human normal immunoglobulin for the first time or, in rare cases, when 

the human normal immunoglobulin product is switched or when there has been a long interval 
since the previous infusion 

- in patients with an untreated infection or underlying chronic inflammation 
 
Hypersensitivity 
 
Hypersensitivity reactions are rare.  
 
Anaphylaxis can develop in patients 
- with undetectable IgA who have anti-IgA antibodies 
- who had tolerated previous treatment with human normal immunoglobulin 

 
In case of shock, standard medical treatment for shock should be implemented. 
 
Thromboembolism 
 
There is clinical evidence of an association between IVIg administration and thromboembolic events 
such as myocardial infarction, cerebral vascular accident (including stroke), pulmonary embolism and 
deep vein thromboses which is assumed to be related to a relative increase in blood viscosity through 
the high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing and 
infusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events 
(such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic 
episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods 
of immobilisation, severely hypovolaemic patients, and patients with diseases which increase blood 
viscosity).  
 
In patients at risk for thromboembolic adverse reactions, IVIg products should be administered at the 
minimum rate of infusion and dose practicable. 
 
Acute renal failure 
 
Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, risk 
factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolaemia, 
overweight, concomitant nephrotoxic medicinal products or age over 65. 
 
Renal parameters should be assessed prior to infusion of IVIg, particularly in patients judged to have a 
potential increased risk for developing acute renal failure, and again at appropriate intervals. In 
patients at risk for acute renal failure, IVIg products should be administered at the minimum rate of 
infusion and dose practicable. In case of renal impairment, IVIg discontinuation should be considered.  
 
While reports of renal dysfunction and acute renal failure have been associated with the use of many 
of the licensed IVIg products containing various excipients such as sucrose, glucose and maltose, 
those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In 
patients at risk, the use of IVIg products that do not contain these excipients may be considered. 
Flebogamma DIF does not contain sucrose, maltose or glucose. 



 
 
 

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Aseptic meningitis syndrome (AMS) 
 
Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment. The 
syndrome usually begins within several hours to 2 days following IVIg treatment. Cerebrospinal fluid 
studies are frequently positive with pleocytosis up to several thousand cells per mm3, predominantly 
from the granulocytic series, and elevated protein levels up to several hundred mg/dl. AMS may occur 
more frequently in association with high-dose (2 g/kg) IVIg treatment.  
 
Patients exhibiting such signs and symptoms should receive a thorough neurological 
examination, including CSF studies, to rule out other causes of meningitis. 
 
Discontinuation of IVIg treatment has resulted in remission of AMS within several days without 
sequelae. 
 
Haemolytic anaemia 
 
IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivo 
coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction 
(Coombs’ test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy 
due to enhanced red blood cells (RBC) sequestration. IVIg recipients should be monitored for clinical 
signs and symptoms of haemolysis. (See section 4.8.) 
 
Neutropenia/Leukopenia 
 
A transient decrease in neutrophil count and/or episodes of neutropenia, sometimes severe, have been 
reported after treatment with IVIgs. This typically occurs within hours or days after IVIg 
administration and resolves spontaneously within 7 to 14 days. 
 
Transfusion related acute lung injury (TRALI) 
 
In patients receiving IVIg, there have been some reports of acute non-cardiogenic pulmonary oedema 
[Transfusion Related Acute Lung Injury (TRALI)]. TRALI is characterised by severe hypoxia, 
dyspnoea, tachypnoea, cyanosis, fever and hypotension. Symptoms of TRALI typically develop during 
or within 6 hours of a transfusion, often within 1 - 2 hours. Therefore, IVIg recipients must be 
monitored for and IVIg infusion must be immediately stopped in case of pulmonary adverse reactions. 
TRALI is a potentially life-threatening condition requiring immediate intensive-care-unit management. 
 
Interference with serological testing 
 
After the administration of immunoglobulin the transitory rise of the various passively transferred 
antibodies in the patient’s blood may result in misleading positive results in serological testing. 
 
Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D may interfere with some 
serological tests for red cell antibodies for example the direct antiglobulin test (DAT, direct Coombs’ 
test). 
 
Transmissible agents 
 
Standard measures to prevent infections resulting from the use of medicinal products prepared from 
human blood or plasma include selection of donors, screening of individual donations and plasma 
pools for specific markers of infection and the inclusion of effective manufacturing steps for the 
inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or 



 
 
 

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plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. 
This also applies to unknown or emerging viruses and other pathogens.  
 
The measures taken are considered effective for enveloped viruses such as human immunodeficiency 
virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped 
hepatitis A and parvovirus B19 viruses. 
 
There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 
transmission with immunoglobulins and it is also assumed that the antibody content makes an 
important contribution to viral safety. 
 
It is strongly recommended that every time that Flebogamma DIF is administered to a patient, the 
name and batch number of the product are recorded in order to maintain a link between the patient 
and the batch of the product. 
 
Sodium content 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per vial of 10 ml, 50 ml, 100 ml 
and 200 ml, that is to say essentially “sodium free”. This medicinal product contains less than 
29,41 mg sodium per vial of 400 ml, equivalent to 1.5% of the WHO recommended maximum daily 
intake of 2 g sodium for an adult. However, depending on the required dose, the patient may receive 
more than 1 vial. 
 
Paediatric population 
It is recommended to monitor vital signs when administering Flebogamma DIF to paediatric patients. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Live attenuated virus vaccines 
 
Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the 
efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After 
administration of this product, an interval of 3 months should elapse before vaccination with live 
attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. 
Therefore patients receiving measles vaccine should have their antibody status checked. 
 
Loop diuretics 
Avoidance of concomitant use of loop diuretics 
 
Paediatric population 
 
It is expected that the same interactions than those mentioned for the adults may be presented by the 
paediatric population. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
The safety of this medicinal product for use in human pregnancy has not been established in 
controlled clinical trials and therefore should only be given with caution to pregnant women and 
breast-feeding mothers. IVIg products have been shown to cross the placenta, increasingly during the 
third trimester. Clinical experience with immunoglobulins suggests that no harmful effects on the 
course of pregnancy, or on the foetus and the neonate are to be expected. 
 



 
 
 

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Breast-feeding 
Immunoglobulins are excreted into human milk. No negative effects on the breastfed 
newborns/infants are anticipated.  
 
Fertility 
Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be 
expected. 
 
4.7 Effects on ability to drive and use machines 
 
The ability to drive and operate machines may be impaired by some adverse reactions, such as 
dizziness, associated with Flebogamma DIF. Patients who experience adverse reactions during 
treatment should wait for these to resolve before driving or operating machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Adverse reactions caused by human normal immunoglobulins (in decreasing frequency) encompass 
(see also section 4.4): 
 
• chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood 

pressure and moderate low back pain 
• reversible haemolytic reactions; especially in those patients with blood groups A, B, and AB 

and (rarely) haemolytic anaemia requiring transfusion 
• (rarely) a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the 

patient has shown no hypersensitivity to previous administration 
• (rarely) transient cutaneous reactions (including cutaneous lupus erythematosus - frequency 

unknown) 
• (very rarely) thromboembolic reactions such as myocardial infarction, stroke, pulmonary 

embolism, deep vein thromboses 
• cases of reversible aseptic meningitis 
• cases of increased serum creatinine level and/or occurrence of acute renal failure 
• cases of Transfusion Related Acute Lung Injury (TRALI) 
 
For safety information with respect to transmissible agents, see section 4.4. 
 
Tabulated list of adverse reactions 
 
The table presented below is according to the MedDRA system organ classification (SOC and 
Preferred Term Level). 
 
Frequencies have been evaluated according to the following convention: 

 
- very common (>1/10) 
- common (>1/100 to <1/10) 
- uncommon (>1/1,000 to <1/100) 
- rare (>1/10,000 to <1/1,000) 
- very rare (<1/10,000)  
- not known (cannot be estimated from the available data) 

 
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
 



 
 
 

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Source of the safety database from clinical trials and post-authorisation safety studies in a total 
of 128 patients exposed to Flebogamma DIF 50 mg/ml (with a total of 1318 infusions) 
 

MedDRA System Organ 
Class (SOC) Adverse reaction 

Frequency 
per 

patient 

Frequency 
per 

infusion 
Infections and infestations Nasopharyngitis Uncommon Uncommon 
Immune system disorders Hypersensitivity Uncommon Rare 
Psychiatric disorders Abnormal behaviour Uncommon Rare 

Nervous system disorders 
Headache Very Common Common 
Dizziness Common Uncommon 
Migraine Uncommon Rare 

Cardiac disorders Tachycardia Common Common Cardiovascular disorder Uncommon Rare 

Vascular disorders 

Diastolic hypotension, Hypotension 
Common 

Common 
Diastolic hypertension, 
Hypertension Uncommon 
Systolic hypertension Uncommon Blood pressure fluctuation, Flushing Rare 

Respiratory, thoracic and 
mediastinal disorders 

Bronchitis, Wheezing Common Uncommon 
Productive cough 

Uncommon 

Uncommon 
Asthma, Cough, Dyspnoea, 
Epistaxis, Nasal discomfort, 
Laryngeal pain 

Rare 

Gastrointestinal disorders Abdominal pain upper, Abdominal pain, Diarrhoea, Nausea, Vomiting Common Uncommon 

Skin and subcutaneous tissue 
disorders 

Urticaria  Common Uncommon Pruritus, Rash pruritic 
Uncommon Dermatitis contact, Hyperhidrosis, 

Rash Rare 

Musculoskeletal and 
connective tissue disorders 

Back pain, Arthralgia, Myalgia Common Uncommon 
Muscle spasms, Neck pain, Pain in 
extremity Uncommon Rare 

Renal and urinary disorders Urinary retention Uncommon Rare 

General disorders and 
administration site conditions 

Pyrexia Very Common Common 
Chills, Injection site reaction, Pain, 
Rigors Common Uncommon 

Asthenia, Chest pain, Infusion site 
erythema, Infusion site 
extravasation, Infusion site 
inflammation, Infusion site pain, 
Injection site oedema, Injection site 
pain, Injection site pruritus, 
Injection site swelling, Oedema 
peripheral 

Uncommon Rare 

Investigations 

Blood pressure systolic increased, 
Body temperature increased, 
Coombs test positive 

Common Uncommon 

Blood pressure systolic decreased 
Uncommon 

Uncommon 
Alanine aminotransferase increased, 
Blood pressure increased Rare 

Injury, poisoning and 
procedural complications Infusion related reaction Uncommon Uncommon 



 
 
 

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MedDRA System Organ 
Class (SOC) Adverse reaction 

Frequency 
per 

patient 

Frequency 
per 

infusion 
Product issues Device dislocation Uncommon Rare 

 
Description of selected adverse reactions  

 
The most reported post-marketing ADRs received since the product was authorised for both 
concentrations were chest pain, flushing, blood pressure increased and decreased, malaise, dyspnoea, 
nausea, vomiting, pyrexia, back pain, headache and chills.  
 
Paediatric population 
 
The safety results for 29 paediatric patients (those ≤ 17 years old) included in the PID studies were 
evaluated. It was observed that the proportion of headache, pyrexia, tachycardia and hypotension in 
children was higher than in adults. Assessment of vital signs in clinical trials of the paediatric 
population did not indicate any pattern of clinically relevant changes.  
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Overdose may lead to fluid overload and hyperviscosity, particularly in patients at risk, including 
elderly patients or patients with cardiac or renal impairment (see section 4.4). 
 
Paediatric population 
 
Information on overdose in children has not been established with Flebogamma DIF. However, as in 
adult population, overdose may lead to fluid overload and hyperviscosity as with any other 
intravenous immunoglobulins.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, 
for intravascular administration, ATC code: J06BA02. 
 
Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of 
antibodies against infectious agents. 
 
Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is 
usually prepared from pooled plasma from not fewer than 1000 donors. It has a distribution of 
immunoglobulin G subclasses closely proportional to that in native human plasma.  
 
Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the 
normal range.  
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 
 
 

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The mechanism of action in indications other than replacement therapy is not fully elucidated, but 
includes immunomodulatory effects. A significant increase in median platelet levels was achieved in a 
clinical trial in chronic ITP patients (64,000/µl) although it did not reach normal levels. 
 
Three clinical trials were performed with Flebogamma DIF, two for replacement therapy in patients 
with primary immunodeficiency (one in both adults and in children above 10 years and another in 
children between 2 to 16 years) and another for immunomodulation in adult patients with immune 
thrombocytopenic purpura. 
 
5.2 Pharmacokinetic properties 
 
Human normal immunoglobulin is immediately and completely bioavailable in the recipient’s 
circulation after intravenous administration. It is distributed relatively rapidly between plasma and 
extravascular fluid, after approximately 3 - 5 days equilibrium is reached between the intra- and 
extravascular compartments. 
 
Flebogamma DIF 50 mg/ml has a half-life of about 30 - 32 days. This half-life may vary from patient 
to patient, in particular in primary immunodeficiency. 
 
IgG and IgG-complexes are broken down in cells of the reticuloendothelial system. 
 
Paediatric population 
 
No differences of the pharmacokinetic properties are expected in the paediatric population. 
 
5.3 Preclinical safety data 
 
Single dose toxicity studies were carried out in rats and mice. The absence of mortality in the 
non-clinical studies performed with Flebogamma DIF with doses up to 2500 mg/kg, and the lack of 
any confirmed relevant adverse sign affecting respiratory, circulatory and central nervous system of 
the treated animals support the safety of Flebogamma DIF. 
 
Repeated dose toxicity testing and embryo-foetal toxicity studies are impracticable due to induction 
of, and interference with antibodies. Effects of the product on the immune system of the newborn 
have not been studied. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
D-sorbitol 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other 
medicinal products, nor with any other IVIg products.  
 
6.3 Shelf life 
 
2 years. 
 



 
 
 

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6.4 Special precautions for storage 
 
Do not store above 30 ºC. 
Do not freeze. 
 
6.5 Nature and contents of container 
 
10 ml, 50 ml, 100 ml, 200 ml or 400 ml solution in a vial (type II glass) with stopper 
(chloro-butyl-rubber). 
 
Pack size: 1 vial 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
The product should be brought to room or body temperature before use. 
 
The solution should be clear or slightly opalescent and colourless or pale yellow. Solutions that are 
cloudy or have deposits should not be used. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/404/001-005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 23 August 2007 
 
Date of latest renewal: 24 April 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
MM/YYYY 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


 
 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Flebogamma DIF 100 mg/ml solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Human normal immunoglobulin (IVIg) 
 
One ml contains: 
Human normal immunoglobulin …………..100 mg 
(purity of at least 97% IgG) 
 
Each vial of 50 ml contains: 5 g of human normal immunoglobulin 
Each vial of 100 ml contains: 10 g of human normal immunoglobulin 
Each vial of 200 ml contains: 20 g of human normal immunoglobulin 
 
Distribution of the IgG subclasses (approx. values): 
IgG1 66.6% 
IgG2 27.9% 
IgG3 3.0% 
IgG4 2.5% 
 
The maximum IgA content is 100 micrograms/ml. 
 
Produced from the plasma of human donors. 
 
Excipient with known effect: 
 
One ml contains 50 mg of D-sorbitol. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for infusion. 
 
The solution is clear or slightly opalescent and colourless or pale yellow. 
 
Flebogamma DIF is isotonic, with an osmolality from 240 to 370 mOsm/kg.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Replacement therapy in adults, children and adolescents (2 - 18 years) in: 
 
- Primary immunodeficiency syndromes (PID) with impaired antibody production 
- Secondary immunodeficiencies (SID) in patients who suffer from severe or recurrent infections, 

ineffective antimicrobial treatment and either proven specific antibody failure (PSAF)* or 
serum IgG level of <4 g/l 

 



 
 
 

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* PSAF= failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide 
and polypeptide antigen vaccines 
 
Immunomodulation in adults, children and adolescents (2 - 18 years) in: 
 
- Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery 

to correct the platelet count 
 
- Guillain Barré syndrome 
 
- Kawasaki disease (in conjunction with acetylsalicylic acid; see 4.2) 

 
- Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) 

 
- Multifocal motor neuropathy (MMN) 
 
4.2 Posology and method of administration 
 
Replacement therapy should be initiated and monitored under the supervision of a physician 
experienced in the treatment of immunodeficiency. 
 
Posology 
 
The dose and dose regimen is dependent on the indication. 
 
The dose may need to be individualised for each patient dependent on the clinical response. Dose 
based on bodyweight may require adjustment in underweight or overweight patients. The following 
dose regimens are given as a guideline. 
 
Replacement therapy in primary immunodeficiency syndromes 
 
The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 
6 g/l or within the normal reference range for the population age. Three to six months are required 
after the initiation of therapy for equilibration (steady-state IgG levels) to occur. The recommended 
starting dose is 0.4 - 0.8 g/kg given once followed by at least 0.2 g/kg given every three to four weeks. 
 
The dose required to achieve a trough level of IgG of 6 g/l is of the order of 0.2 - 0.8 g/kg/month. The 
dose interval when steady state has been reached varies from 3 - 4 weeks. 
 
IgG trough levels should be measured and assessed in conjunction with the incidence of infection. To 
reduce the rate of bacterial infections, it may be necessary to increase the dosage and aim for higher 
trough levels. 
 
Secondary immunodeficiencies (as defined in 4.1) 
 
The recommended dose is 0.2 - 0.4 g/kg every three to four weeks. 
 
IgG trough levels should be measured and assessed in conjunction with the incidence of infection. 
Dose should be adjusted as necessary to achieve optimal protection against infections, an increase 
may be necessary in patients with persisting infection; a dose decrease can be considered when the 
patient remains infection free. 
 



 
 
 

 - 17 - 
 

Primary immune thrombocytopenia 
 
There are two alternative treatment schedules: 
• 0.8 - 1 g/kg given on day one; this dose may be repeated once within 3 days. 
• 0.4 g/kg given daily for two to five days.  
 
The treatment can be repeated if relapse occurs. 
 
Guillain Barré syndrome 
 
0.4 g/kg/day over 5 days (possible repeat of dosing in case of relapse). 
 
Kawasaki disease 
 
2.0 g/kg should be administered as a single dose. Patients should receive concomitant treatment with 
acetylsalicylic acid. 
 
Chronic inflammatory demyelinating polyneuropathy (CIDP) 
 
Starting dose: 2 g/kg divided over 2 - 5 consecutive days. 
Maintenance doses: 1 g/kg over 1 - 2 consecutive days every 3 weeks. 
The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 
6 months, the treatment should be discontinued. 
If the treatment is effective long term treatment should be subject to the physicians discretion based 
upon the patient response and maintenance response. The dosing and intervals may have to be 
adapted according to the individual course of the disease. 
 
Multifocal motor neuropathy (MMN) 
 
Starting dose: 2 g/kg divided over 2 - 5 consecutive days. 
Maintenance dose: 1 g/kg every 2 to 4 weeks or 2 g/kg every 4 to 8 weeks. 
The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 
6 months, the treatment should be discontinued. 
If the treatment is effective long term treatment should be subject to the physicians discretion based 
upon the patient response and maintenance response. The dosing and intervals may have to be 
adapted according to the individual course of the disease. 
 
The dose recommendations are summarised in the following table: 

 
Indication Dose Frequency of injections 

Replacement therapy:   
Primary immunodeficiency syndromes 
 
 
 
 
 

Starting dose: 
0.4 - 0.8 g/kg 
 
Maintenance 
dose: 
0.2 - 0.8 g/kg 

 
 
 
 
 
every 3 - 4 weeks  

Secondary immunodeficiencies (as defined in 
4.1) 

0.2 - 0.4 g/kg 
 

every 3 - 4 weeks 
 



 
 
 

 - 18 - 
 

Immunomodulation:   
Primary immune thrombocytopenia 
 
 
 
 

0.8 - 1 g/kg 
 
or 

 
0.4 g/kg/d 

on day 1, possibly repeated once 
within 3 days 
 
 
for 2 - 5 days 

Guillain Barré syndrome 0.4 g/kg/d for 5 days 

Kawasaki disease 2 g/kg in one dose in association with 
acetylsalicylic acid 

Chronic inflammatory demyelinating 
polyradiculoneuropathy (CIDP) 

Starting dose: 
2 g/kg 
 
Maintenance 
dose: 
1 g/kg 

 
in divided doses over 2 - 5 days 
 
 
 
every 3 weeks over 1 - 2 days 

Multifocal motor neuropathy (MMN) Starting dose: 
2 g/kg 
 
 
Maintenance 
dose: 
1 g/kg 
 
or 
 
2 g/kg 

 
in divided doses over 
2 - 5 consecutive days 
 
 
 
every 2 - 4 weeks 
 
 
 
every 4 - 8 weeks in divided doses 
over 2 - 5 days 

 
Paediatric population 
 
Flebogamma DIF 100 mg/ml is contraindicated in children aged 0 to 2 years (see section 4.3). 
 
The posology in children and adolescents (2 - 18 years) is not different to that of adults as the 
posology for each indication is given by body weight and adjusted to the clinical outcome of the 
above mentioned conditions. 
 
Hepatic impairment 
No evidence is available to require a dose adjustment. 
 
Renal impairment 
No dose adjustment unless clinically warranted, see section 4.4. 
 
Elderly 
No dose adjustment unless clinically warranted, see section 4.4. 
 
Method of administration 
 
For intravenous use. 
Flebogamma DIF 100 mg/ml should be infused intravenously at an initial rate of 0.01 ml/kg/min for 
the first thirty minutes. See section 4.4. In case of adverse reaction, either the rate of administration 
must be reduced or the infusion stopped. If well 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 



 
 
 

 - 19 - 
 

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 (see section 4.4). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance (human immunoglobulins) or to any of the excipients (see 
sections 4.4 and 6.1). 
 
Fructose intolerance (see section 4.4).  
In babies and young children (aged 0 - 2 years) hereditary fructose intolerance (HFI) may not yet be 
diagnosed and may be fatal, thus, they must not receive this medicinal product. 
 
Patients with selective IgA deficiency who developed antibodies to IgA, as administering an 
IgA-containing product can result in anaphylaxis. 
 
4.4 Special warnings and precautions for use 
 
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 persons more than 2 years old with HFI, a spontaneous aversion for fructose-containing 
foods develops and may be combined with the onset of symptoms (vomiting, gastro-intestinal 
disorders, apathy, height and weight retardation). Therefore a detailed history with regard to 
HFI symptoms has to be taken of each patient prior to receiving Flebogamma DIF.  
In case of inadvertent administration and suspicion of 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.  

 
Traceability 
In order to improve the traceability of biological medicinal products, the name and the batch 
number of the administered product should be clearly recorded. 
 
Precautions for use 
Potential complications can often be avoided by ensuring that patients: 
- are not sensitive to human normal immunoglobulin by initially injecting the product slowly (at 

an initial rate of 0.01 ml/kg/min) 
- are carefully monitored for any symptoms throughout the infusion period. In particular, patients 

naive to human normal immunoglobulin, patients switched from an alternative IVIg product or 
when there has been a long interval since the previous infusion should be monitored at the 
hospital during the first infusion and for the first hour after the first infusion, in order to detect 
potential adverse signs. All other patients should be observed for at least 20 minutes after 
administration 

 



 
 
 

 - 20 - 
 

In all patients, IVIg administration requires: 
- adequate hydration prior to the initiation of the infusion of IVIg 
- monitoring of urine output 
- monitoring of serum creatinine levels 
- avoidance of concomitant use of loop diuretics (see 4.5) 
 
In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. 
The treatment required depends on the nature and severity of the adverse reaction. 
 
Infusion reaction 
 
Certain adverse reactions (e.g. headache, flushing, chills, myalgia, wheezing, tachycardia, lower back 
pain, nausea, and hypotension) may be related to the rate of infusion. The recommended infusion rate 
given under section 4.2 must be closely followed. Patients must be closely monitored and carefully 
observed for any symptoms throughout the infusion period. 
 
Adverse reactions may occur more frequently 
- in patients who receive human normal immunoglobulin for the first time or, in rare cases, when 

the human normal immunoglobulin product is switched or when there has been a long interval 
since the previous infusion 

- in patients with an untreated infection or underlying chronic inflammation 
 
Hypersensitivity 
 
Hypersensitivity reactions are rare.  
 
Anaphylaxis can develop in patients 
- with undetectable IgA who have anti-IgA antibodies 
- who had tolerated previous treatment with human normal immunoglobulin 
 
In case of shock, standard medical treatment for shock should be implemented. 
 
Thromboembolism 
 
There is clinical evidence of an association between IVIg administration and thromboembolic events 
such as myocardial infarction, cerebral vascular accident (including stroke), pulmonary embolism and 
deep vein thromboses which is assumed to be related to a relative increase in blood viscosity through 
the high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing and 
infusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events 
(such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic 
episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods 
of immobilisation, severely hypovolaemic patients, and patients with diseases which increase blood 
viscosity).  
 
In patients at risk for thromboembolic adverse reactions, IVIg products should be administered at the 
minimum rate of infusion and dose practicable. 
 
Acute renal failure 
 
Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, risk 
factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolaemia, 
overweight, concomitant nephrotoxic medicinal products or age over 65. 
 



 
 
 

 - 21 - 
 

Renal parameters should be assessed prior to infusion of IVIg, particularly in patients judged to have a 
potential increased risk for developing acute renal failure, and again at appropriate intervals. In 
patients at risk for acute renal failure, IVIg products should be administered at the minimum rate of 
infusion and dose practicable. In case of renal impairment, IVIg discontinuation should be considered. 
 
While reports of renal dysfunction and acute renal failure have been associated with the use of many 
of the licensed IVIg products containing various excipients such as sucrose, glucose and maltose, 
those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In 
patients at risk, the use of IVIg products that do not contain these excipients may be considered. 
Flebogamma DIF does not contain sucrose, maltose or glucose. 
 
Aseptic meningitis syndrome (AMS) 
 
Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment. The 
syndrome usually begins within several hours to 2 days following IVIg treatment. Cerebrospinal fluid 
studies are frequently positive with pleocytosis up to several thousand cells per mm3, predominantly 
from the granulocytic series, and elevated protein levels up to several hundred mg/dl. AMS may occur 
more frequently in association with high-dose (2 g/kg) IVIg treatment. 
 
Patients exhibiting such signs and symptoms should receive a thorough neurological 
examination, including CSF studies, to rule out other causes of meningitis. 
 
Discontinuation of IVIg treatment has resulted in remission of AMS within several days without 
sequelae. 
 
Haemolytic anaemia 
 
IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivo 
coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction 
(Coomb’s test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy 
due to enhanced red blood cells (RBC) sequestration. IVIg recipients should be monitored for clinical 
signs and symptoms of haemolysis. (See section 4.8) 
 
Neutropenia/Leukopenia 
 
A transient decrease in neutrophil count and/or episodes of neutropenia, sometimes severe, have been 
reported after treatment with IVIgs. This typically occurs within hours or days after IVIg 
administration and resolves spontaneously within 7 to 14 days. 
 
Transfusion related acute lung injury (TRALI) 
 
In patients receiving IVIg, there have been some reports of acute non-cardiogenic pulmonary oedema 
[Transfusion Related Acute Lung Injury (TRALI)]. TRALI is characterised by severe hypoxia, 
dyspnoea, tachypnoea, cyanosis, fever and hypotension. Symptoms of TRALI typically develop 
during or within 6 hours of a transfusion, often within 1 - 2 hours. Therefore, IVIg recipients must be 
monitored for and IVIg infusion must be immediately stopped in case of pulmonary adverse reactions. 
TRALI is a potentially life-threatening condition requiring immediate intensive-care-unit 
management. 
 
Interference with serological testing 
 
After the administration of immunoglobulin the transitory rise of the various passively transferred 
antibodies in the patient’s blood may result in misleading positive results in serological testing. 



 
 
 

 - 22 - 
 

 
Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D, may interfere with some 
serological tests for red cell antibodies for example the direct antiglobulin test (DAT, direct Coomb’s 
test). 
 
Transmissible agents 
 
Standard measures to prevent infections resulting from the use of medicinal products prepared from 
human blood or plasma include selection of donors, screening of individual donations and plasma 
pools for specific markers of infection and the inclusion of effective manufacturing steps for the 
inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or 
plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. 
This also applies to unknown or emerging viruses and other pathogens.  
 
The measures taken are considered effective for enveloped viruses such as human immunodeficiency 
virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped 
hepatitis A and parvovirus B19 viruses. 
 
There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 
transmission with immunoglobulins and it is also assumed that the antibody content makes an 
important contribution to viral safety. 
 
It is strongly recommended that every time that Flebogamma DIF is administered to a patient, the 
name and batch number of the product are recorded in order to maintain a link between the patient 
and the batch of the product. 
 
Sodium content 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 
“sodium free”. However, depending on the required dose, the patient may receive more than 1 vial. 
 
Post-authorisation Safety Study  
 
A Post-Authorisation Safety Study suggested a higher rate of infusions associated with potentially 
related adverse events for Flebogamma DIF 100 mg/ml compared to Flebogamma DIF 50 mg/ml (see 
section 5.1). 
 
Paediatric population 
It is recommended to monitor vital signs when administering Flebogamma DIF to paediatric patients. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Live attenuated virus vaccines 
 
Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the 
efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After 
administration of this product, an interval of 3 months should elapse before vaccination with live 
attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. 
Therefore patients receiving measles vaccine should have their antibody status checked. 
 
Loop diuretics 
Avoidance of concomitant use of loop diuretics 



 
 
 

 - 23 - 
 

 
Paediatric population 
 
It is expected that the same interactions than those mentioned for the adults may be presented by the 
paediatric population. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
The safety of this medicinal product for use in human pregnancy has not been established in 
controlled clinical trials and therefore should only be given with caution to pregnant women and 
breast-feeding mothers. IVIg products have been shown to cross the placenta, increasingly during the 
third trimester. Clinical experience with immunoglobulins suggests that no harmful effects on the 
course of pregnancy, or on the foetus and the neonate are to be expected. 
 
Breast-feeding 
Immunoglobulins are excreted into human milk. No negative effects on the breastfed 
newborns/infants are anticipated.  
 
Fertility 
Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be 
expected. 
 
4.7 Effects on ability to drive and use machines 
 
The ability to drive and operate machines may be impaired by some adverse reactions, such as 
dizziness, associated with Flebogamma DIF. Patients who experience adverse reactions during 
treatment should wait for these to resolve before driving or operating machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 

 
Adverse reactions caused by human normal immunoglobulins (in decreasing frequency) encompass 
(see also section 4.4): 
 
• chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood 

pressure and moderate low back pain 
• reversible haemolytic reactions; especially in those patients with blood groups A, B, and AB 

and (rarely) haemolytic anaemia requiring transfusion 
• (rarely) a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the 

patient has shown no hypersensitivity to previous administration 
• (rarely) transient cutaneous reactions (including cutaneous lupus erythematosus - frequency 

unknown) 
• (very rarely) thromboembolic reactions such as myocardial infarction, stroke, pulmonary 

embolism, deep vein thromboses 
• cases of reversible aseptic meningitis 
• cases of increased serum creatinine level and/or occurrence of acute renal failure 
• cases of Transfusion Related Acute Lung Injury (TRALI) 
 
For safety information with respect to transmissible agents, see section 4.4. 
 



 
 
 

 - 24 - 
 

Tabulated list of adverse reactions 
 
Increase in the frequency of adverse reactions through the clinical trials likely related to the increased 
infusion rate has been observed (see section 4.2). 
 
The table presented below is according to the MedDRA system organ classification (SOC and 
Preferred Term Level).  
 
Frequencies have been evaluated according to the following convention: 

 
- very common (>1/10) 
- common (>1/100 to <1/10) 
- uncommon (>1/1,000 to <1/100) 
- rare (>1/10,000 to <1/1,000) 
- very rare (<1/10,000) 
- not known (cannot be estimated from the available data) 

 
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
 
Source of the safety database from clinical trials and post-authorisation safety studies in 
a total of 160 patients exposed to Flebogamma DIF 100 mg/ml (with a total of 
915 infusions) 
 

MedDRA System Organ 
Class (SOC) 

Adverse reaction 
 

Frequency 
per 

patient 

Frequency 
per 

infusion 

Infections and infestations Influenza, Meningitis aseptic,  Urinary tract infection Uncommon Uncommon 

Blood and lymphatic system 
disorders Bicytopenia, Leukopenia Uncommon Uncommon 

Immune system disorders Hypersensitivity Common Uncommon 
Metabolism and nutrition 
disorders Decreased appetite Uncommon Uncommon 

Psychiatric disorders Insomnia, Restlessness Uncommon Uncommon 

Nervous system disorders 
Headache Very common Very common 
Dizziness, Tremor Common Uncommon Radiculopathy, Syncope Uncommon 

Eye disorders 
Photophobia Common 

Uncommon Conjunctivitis, Maculopathy, Vision 
blurred Uncommon 

Ear and labyrinth disorders Vertigo Common Uncommon Ear pain Uncommon 

Cardiac disorders Tachycardia Common Common Cyanosis Uncommon Uncommon 

Vascular disorders 

Hypotension Common Common Diastolic hypertension, Hypertension 
Uncommon Flushing, Haematoma, Lymphoedema, 

Systolic hypertension, Thrombosis Uncommon 

Respiratory, thoracic and 
mediastinal disorders 

Wheezing Common 

Uncommon Epistaxis, Nasal congestion, Upper-airway cough syndrome, Sinus 
pain, Dyspnoea 

Uncommon 

Gastrointestinal disorders Nausea Very common Common 



 
 
 

 - 25 - 
 

MedDRA System Organ 
Class (SOC) 

Adverse reaction 
 

Frequency 
per 

patient 

Frequency 
per 

infusion 
Vomiting 

Common Abdominal pain, Abdominal pain 
upper, Diarrhoea, Flatulence Uncommon Abdominal discomfort, Abdominal 
distension, Dry mouth, Haematemesis Uncommon 

Skin and subcutaneous 
tissue disorders 

Pruritus, Rash Common 

Uncommon Acne, Alopecia, Ecchymosis, Erythema, Hyperhidrosis, Palmar 
erythema, Purpura 

Uncommon 

Musculoskeletal and 
connective tissue disorders 

Back pain, Myalgia 

Common 

Common 
Limb discomfort, Muscle spasms, 
Muscle tightness, Neck pain, Pain in 
extremity Uncommon 

Arthralgia, Musculoskeletal discomfort Uncommon 

General disorders and 
administration site 
conditions 

Pyrexia, Rigors Very common Common Chills 

Common Chest discomfort, Chest pain, Fatigue, Feeling cold, Infusion site reaction, 
Malaise, Oedema peripheral, Pain 

Uncommon Feeling jittery, Influenza like illness, 
Infusion site erythema, Infusion site 
pain, General physical health 
deterioration 

Uncommon 

Investigations 

Body temperature increased 

Common 

Common 
Blood pressure diastolic decreased, 
Blood pressure increased, Blood 
pressure systolic increased, Heart rate 
increased Uncommon 
Blood pressure systolic decreased, 
Haemoglobin decreased, Heart rate 
decreased, Reticulocyte count increased 

Uncommon 

Injury, poisoning and 
procedural complications 

Contusion Common Uncommon Infusion related reaction Uncommon 
 
Description of selected adverse reactions  
 
The most reported post-marketing ADRs received since the product was authorised for both 
concentrations were chest pain, flushing, blood pressure increased and decreased, malaise, dyspnoea, 
nausea, vomiting, pyrexia, back pain, headache and chills.  
 
Paediatric population 
 
The safety results for 4 paediatric patients (those ≤ 17 years old) included in the PID study and the 
results for the 13 children (aged 3 to 16 years old) included in the ITP study were evaluated. It was 
observed that the proportion of headache, chills, pyrexia, nausea, vomiting, hypotension, heart rate 
increase and back pain in children was higher than in adults. Cyanosis was reported in one child but 
not in adults. Assessment of vital signs in clinical trials of the paediatric population did not indicate 
any pattern of clinically relevant changes. 
 



 
 
 

 - 26 - 
 

Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Overdose may lead to fluid overload and hyperviscosity, particularly in patients at risk, including 
elderly patients or patients with cardiac or renal impairment (see section 4.4). 
 
Paediatric population 
 
Information on overdose in children has not been established with Flebogamma DIF. However, as in 
adult population, overdose may lead to fluid overload and hyperviscosity as with any other 
intravenous immunoglobulins.  
 
 
5.  PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, 
for intravascular administration, ATC code: J06BA02. 
 
Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of 
antibodies against infectious agents. 
 
Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is 
usually prepared from pooled plasma from not fewer than 1000 donors. It has a distribution of 
immunoglobulin G subclasses closely proportional to that in native human plasma.  
 
Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the 
normal range.  
 
The mechanism of action in indications other than replacement therapy is not fully elucidated, but 
includes immunomodulatory effects.  
 
Three clinical trials were performed with Flebogamma DIF, one for replacement therapy in patients 
with primary immunodeficiency (in both adults and in children above 6 years) and two for 
immunomodulation, in patients with immune thrombocytopenic purpura (one in adult patients and 
another in both adults and in children between 3 and 16 years). 
 
In a Post-authorisation Safety Study that included 66 patients, Flebogamma DIF 100 mg/ml showed a 
higher rate (18.46%, n=24/130) of infusions associated with potentially related adverse events than 
Flebogamma DIF 50 mg/ml (2.22%, n=3/135). However one subject treated with Flebogamma DIF 
100 mg/ml presented mild episodes of headache in all infusions and one more patient had 2 episodes 
of pyrexia in 2 infusions. It is worth considering that these 2 subjects contributed to the higher 
frequency of infusions with reactions in this group. There were no other subjects with more than 
1 infusion with adverse reactions in both groups. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 
 
 

 - 27 - 
 

5.2 Pharmacokinetic properties 
 
Human normal immunoglobulin is immediately and completely bioavailable in the recipient’s 
circulation after intravenous administration. It is distributed relatively rapidly between plasma and 
extravascular fluid, after approximately 3 - 5 days equilibrium is reached between the intra- and 
extravascular compartments. 
 
Flebogamma DIF 100 mg/ml has a half-life of about 34 - 37 days. This half-life may vary from patient 
to patient, in particular in primary immunodeficiency. 
 
IgG and IgG-complexes are broken down in cells of the reticuloendothelial system. 
 
Paediatric population 
 
No differences of the pharmacokinetic properties are expected in the paediatric population. 
  
5.3 Preclinical safety data 
 
Single dose toxicity studies were carried out in rats and mice. The absence of mortality in the 
non-clinical studies performed with Flebogamma DIF with doses up to 2500 mg/kg, and the lack of 
any confirmed relevant adverse sign affecting respiratory, circulatory and central nervous system of 
the treated animals support the safety of Flebogamma DIF. 
 
Repeated dose toxicity testing and embryo-foetal toxicity studies are impracticable due to induction 
of, and interference with antibodies. Effects of the product on the immune system of the newborn 
have not been studied. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
D-sorbitol 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other 
medicinal products, nor with any other IVIg products. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30 ºC. 
Do not freeze. 
 
6.5 Nature and contents of container 
 
50 ml, 100 ml or 200 ml solution in a vial (type II glass) with stopper (chloro-butyl-rubber). 
 
Pack size: 1 vial 



 
 
 

 - 28 - 
 

 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
The product should be brought to room or body temperature before use. 
 
The solution should be clear or slightly opalescent and colourless or pale yellow. Solutions that are 
cloudy or have deposits should not be used. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/404/006-008 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 23 August 2007 
 
Date of latest renewal: 24 April 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
MM/YYYY 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


 
 
 

 - 29 - 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 

SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 
BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



 
 
 

 - 30 - 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
Instituto Grifols, S.A. 
Polígono Levante 
Can Guasc, 2,  
E-08150 Parets del Vallès 
Barcelona, Spain 
 
Name and address of the manufacturer responsible for batch release 
 
Instituto Grifols, S.A. 
Polígono Levante 
Can Guasc, 2 
E-08150 Parets del Vallès 
Barcelona, Spain 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
• Official batch release 
 
In accordance with Article 114 of Directive 2001/83/EC, the official batch release will be undertaken 
by a state laboratory or a laboratory designated for that purpose. 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The marketing authorisation holder shall submit periodic safety update reports for this product 
in accordance with the requirements set out in the list of Union reference dates (EURD list) 
provided for under Article 107c(7) of Directive 2001/83/EC and published on the European 
medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 

 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 



 
 
 

 - 31 - 
 

• Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same 
time. 
 



 
 
 

 - 32 - 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET  
 



 
 
 

 - 33 - 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 



 
 
 

 - 34 - 
 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON (0.5 g) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Flebogamma DIF 50 mg/ml solution for infusion 
Human normal immunoglobulin (IVIg) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One ml contains 50 mg of human normal immunoglobulin (IVIg) of which at least 97% is IgG. 
 
0.5 g / 10 ml 
 
 
3. LIST OF EXCIPIENTS 
 
D-sorbitol, water for injections.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for infusion. 
 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use. 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



 
 
 

 - 35 - 
 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30 ºC. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/404/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



 
 
 

 - 36 - 
 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON (2.5 g, 5 g, 10 g and 20 g) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Flebogamma DIF 50 mg/ml solution for infusion 
Human normal immunoglobulin (IVIg) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One ml contains 50 mg of human normal immunoglobulin (IVIg) of which at least 97% is IgG. 
The maximum IgA content is 50 micrograms/ml. 
2.5 g / 50 ml 
5 g / 100 ml 
10 g / 200 ml 
20 g / 400 ml 
 
 
3. LIST OF EXCIPIENTS 
 
D-sorbitol, water for injections. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for infusion. 
 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use. 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 



 
 
 

 - 37 - 
 

 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30 ºC. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/404/002 
EU/1/07/404/003 
EU/1/07/404/004 
EU/1/07/404/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



 
 
 

 - 38 - 
 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



 
 
 

 - 39 - 
 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
VIAL LABEL (5 g, 10 g and 20 g) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Flebogamma DIF 50 mg/ml solution for infusion 
Human normal immunoglobulin (IVIg) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One ml contains 50 mg of human normal immunoglobulin (IVIg) of which at least 97% is IgG. 
 
 
3. LIST OF EXCIPIENTS 
 
D-sorbitol, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for infusion 
 
5 g / 100 ml 
10 g / 200 ml 
20 g / 400 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use 
 
Read the package leaflet before use. 
 
To hang pull here 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 



 
 
 

 - 40 - 
 

 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30 ºC. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 



 
 
 

 - 41 - 
 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
 
VIAL LABEL (0.5 g and 2.5 g) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Flebogamma DIF 50 mg/ml solution for infusion 
Human normal immunoglobulin (IVIg) 
For intravenous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 g / 10 ml 
2.5 g / 50 ml 
 
 
6. OTHER 
 
To hang pull here



 
 
 

 - 42 - 
 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON (5 g, 10 g and 20 g) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Flebogamma DIF 100 mg/ml solution for infusion 
Human normal immunoglobulin (IVIg) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One ml contains 100 mg of human normal immunoglobulin (IVIg) of which at least 97% is IgG. 
The maximum IgA content is 100 micrograms/ml. 
5 g / 50 ml 
10 g / 100 ml 
20 g / 200 ml 
 
 
3. LIST OF EXCIPIENTS 
 
D-sorbitol, water for injections. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for infusion 
 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 



 
 
 

 - 43 - 
 

 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30 ºC. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/404/006 
EU/1/07/404/007 
EU/1/07/404/008 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 



 
 
 

 - 44 - 
 

SN: 
NN:



 
 
 

 - 45 - 
 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
VIAL LABEL (5 g) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Flebogamma DIF 100 mg/ml solution for infusion 
Human normal immunoglobulin (IVIg) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for infusion 
 
5 g / 50 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
To hang pull here 
For intravenous use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 



 
 
 

 - 46 - 
 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 



 
 
 

 - 47 - 
 

 
 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
VIAL LABEL (10 g and 20 g) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Flebogamma DIF 100 mg/ml solution for infusion 
Human normal immunoglobulin (IVIg) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One ml contains 100 mg of human normal immunoglobulin (IVIg) of which at least 97% is IgG. 
 
 
3. LIST OF EXCIPIENTS 
 
D-sorbitol, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for infusion 
 
10 g / 100 ml 
20 g / 200 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
To hang pull here 
For intravenous use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



 
 
 

 - 48 - 
 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30 ºC. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 



 
 
 

 - 49 - 
 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 



 
 
 

 - 50 - 
 

Package leaflet: Information for the user 
 

Flebogamma DIF 50 mg/ml solution for infusion 
Human normal immunoglobulin (IVIg) 

 
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. 
 
What is in this leaflet: 
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. How to store 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, highly purified protein extracted from 
human plasma (part of the blood of donors). This medicine belongs to 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 (2 - 18 years) who do not have sufficient antibodies 
(Flebogamma DIF is used as replacement therapy). There are two groups: 
 
• Patients with Primary Immunodeficiency Syndromes (PID), an inborn lack of antibodies 

(group 1) 
 

• Patients with Secondary Immunodeficiency Syndromes (SID) with severe or recurrent 
infections, ineffective antimicrobial treatment and either proven specific antibody failure 
(PSAF)* or serum IgG level of <4 g/l (group 2)  

 
*PSAF= failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide 
and polypeptide antigen vaccines. 
 
Treatment of adults, children and adolescents (2 - 18 years) with certain autoimmune disorders 
(immunomodulation). There are five groups: 
 
• Primary immune thrombocytopenia (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.  



 
 
 

 - 51 - 
 

 
• Guillain Barré syndrome, where the immune system damages the nerves and hinders them from 

working properly. 
 
• Kawasaki disease (in this case in conjunction with acetylsalicylic acid therapy), an illness in 

children where the blood vessels (arteries) in the body become enlarged. 
 

• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a rare and progressive 
disease causing limb weakness, numbness, pain and fatigue. 
 

• Multifocal motor neuropathy (MMN), a rare disease causing slow progressive asymmetric limb 
weakness 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 normal immunoglobulin or any of the other ingredients of this 

medicine (listed in section 6). 
 
- If you do not have enough immunoglobulins of the type IgA in your blood or have developed 

antibodies to IgA. 
 
- If you have fructose intolerance, a quite rare genetic condition where the enzyme for breaking 

down fructose is not produced. In babies and young children (aged 0 - 2 years) hereditary 
fructose intolerance may not yet be diagnosed and may be fatal, thus, they must not receive this 
medicine (see special warnings about excipients at the end of this section). 

 
Warnings and precautions  
 
Talk to your doctor, pharmacist or nurse before using Flebogamma DIF. 
 
Certain side effects may occur more frequently: 
• in case of high rate of infusion. 
• 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. 
 
Patients with pre-existing risk factors 
 
Please tell your doctor if you have any other condition and/or illness, as control is required in patients 
with pre-existing risk factors for thrombotic events (formation of blood clots inside your blood). In 
particular, tell your doctor if you have: 
• diabetes 
• high blood pressure 
• history of vascular disease or thrombosis 
• overweight  
• blood volume decrease 



 
 
 

 - 52 - 
 

• diseases which increase blood viscosity 
• age over 65 
 
Patients with a kidney problem 
 
If you have a renal disease and you are receiving Flebogamma DIF for the first time, you may suffer a 
problem in your kidneys. 
 
Your doctor will consider your risk factors and take measures such as to decrease the rate of infusion 
or to stop the treatment. 
 
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.  
 
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, 
 

• the testing of each donation and pools of plasma for signs of virus/infections, 
 
• the inclusion of 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. 
 
It is strongly recommended that every time you receive a dose of Flebogamma DIF, the name and 
batch number of the medicine (stated on the label and carton after Lot) are recorded in order to 
maintain a record of the batches used. 
 
Children and adolescents 
 
Vital signs (body temperature, blood pressure, heart rate and respiratory rate) should be observed 
during the infusion of Flebogamma DIF. 
 
Other medicines and Flebogamma DIF 
 
 Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.  
 



 
 
 

 - 53 - 
 

• Effects on vaccines: Flebogamma DIF may reduce the effectiveness of certain types of vaccines 
(live attenuated virus vaccines). In 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 
case of measles, the period is up to 1 year. 

 
 You should avoid the concomitant use of medicines that increase the excretion of water from 

your body (loop diuretics) during treatment with Flebogamma DIF. 
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, 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 (for example dizziness or nausea) during treatment, which might 
affect the ability to drive and use machines. 
 
Flebogamma DIF contains sorbitol 
 
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 persons more than 2 years old with problems to tolerate fructose, a spontaneous reaction for 
fructose-containing foods develops which may have the following symptoms: vomiting, 
gastro-intestinal disorders, apathy, height and weight retardation. Therefore, patients should be 
examined for the symptoms of Hereditary Fructose Intolerance prior to receiving 
Flebogamma DIF. 
 
Flebogamma DIF contains sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per vial of 10 ml, 50 ml, 100 ml and 200 ml, 
that is to say essentially “sodium free”. This medicine contains less than 29,41 mg sodium (main 
component of cooking/table salt) in each vial of 400 ml. This is equivalent to 1.5% of the 
recommended maximum daily dietary intake of sodium for an adult. However, depending on the 
required dose, the patient may receive more than 1 vial. 
 
 
3. How to use Flebogamma DIF 
 
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 - 0.02 ml/kg/min). Depending on how comfortable you feel, your doctor may then gradually 
increase the infusion rate (up to 0.1 ml/kg/min). 
 



 
 
 

 - 54 - 
 

Use in children of more than 2 years old 
 
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 heart or 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. 
 
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, this medicine can cause side effects, although not everybody gets them. 
 
In rare and isolated cases, the following side effects have been reported with immunoglobulin 
preparations. Seek medical care with no delay 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 (which signs are rash, 

hypotension, palpitation, wheezing, coughing, sneezing and difficulty breathing among others), 
even if you have shown no hypersensitivity to previous administration. 

• Cases of temporary non-infective meningitis (which signs are headache, fear or intolerance of 
light, stiff neck). 

• Cases of temporary reduction in the number of the red cells in the blood (reversible haemolytic 
anaemia/haemolysis). 

• Cases of transient cutaneous reactions (side effects on your skin). 
• Increase in serum creatinine level (a test which measures your kidney function) and/or acute 

renal failure (which signs are low back pain, fatigue, decrease in the amount of urine). 
• Thromboembolic reactions such as myocardial infarction (tight band around the chest with 

feeling like your heart is beating too fast), stroke (muscle weakness in the face, arm, or leg, 
trouble speaking or understanding others who are speaking), pulmonary embolism (shortness of 
breath, chest pain and fatigue), deep vein thromboses (pain and swelling in an extremity). 

• Cases of transfusion related acute lung injury (TRALI) that causes hypoxia (lack of oxygen), 
dyspnoea (difficulty in breathing), tachypnoea (rapid 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 (body temperature increased) 
● tachycardia (acceleration of the heart activity) 
● hypotension 
 



 
 
 

 - 55 - 
 

Uncommon (may affect up to 1 in 100 infusions): 
● bronchitis 
• nasopharyngitis 
• dizziness (motion sickness) 
• hypertension 
• blood pressure increased 
● wheezing 
• productive cough 
● abdominal pain (including abdominal pain upper)  
● diarrhoea 
● vomiting 
● nausea 
● urticaria 
• pruritus (itching) 
• rash (eruption of the skin) 
● back pain 
● myalgia (muscle pain) 
● arthralgia (joint pain)  
● rigors (cold shivering sensation) or chills 
● pain 
● injection site reaction 
● Coombs test positive 
• blood pressure decreased 
 
Rare (may affect up to 1 in 1000 infusions): 
• hypersensitivity 
• abnormal behaviour 
• migraine 
• blood pressure fluctuation 
• flushing (to blush) 
• cough 
• asthma 
• dyspnoea (difficulty in breathing) 
• epistaxis (haemorrhage from the nose) 
• nasal discomfort 
• laryngeal pain 
• dermatitis contact 
• hyperhidrosis (excessive sweating) 
• rash 
• muscle spasms 
• neck pain 
• pain in extremity 
• urinary retention 
• asthenia (fatigue) 
• chest pain 
• infusion site reactions (erythema, extravasation, inflammation, pain) 
• injection site reactions (including injection site oedema, pain, pruritus and swelling) 
• oedema peripheral 
• alanine aminotransferase (hepatic transaminase) increased 
• device dislocation 
 



 
 
 

 - 56 - 
 

Additional side effects in children and adolescents 
 
It was observed that the proportion of headache, fever, heart rate increased and low blood pressure in 
children was higher than in adults. 
 
Reporting of side effects 
If you get 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 via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store 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 ºC. Do not freeze. 
 
The solution should be clear or slightly opalescent. Do not use this medicine if you notice that the 
solution is cloudy or has deposits. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Flebogamma DIF contains 
 
- The active substance is human normal immunoglobulin (IVIg). One ml contains 50 mg of 

human normal immunoglobulin, of which at least 97% is IgG. 
 

Each vial of 10 ml contains: 0.5 g of human normal immunoglobulin 
Each vial of 50 ml contains: 2.5 g of human normal immunoglobulin 
Each vial of 100 ml contains: 5 g of human normal immunoglobulin 
Each vial of 200 ml contains: 10 g of human normal immunoglobulin 
Each vial of 400 ml contains: 20 g of human normal immunoglobulin 

 
The percentage of IgG subclasses is approximately 66.6% IgG1, 28.5% IgG2, 2.7% IgG3 and 
2.2% IgG4. It contains trace amounts of IgA (lower than 50 micrograms/ml). 

 
- The other ingredients are sorbitol and water for injections (see section 2 for further information 

about ingredients). 
 
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 0.5 g/10 ml, 2.5 g/50 ml, 5 g/100 ml, 10 g/200 ml and 20 g/400 ml 
vials. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 
 
 

 - 57 - 
 

Pack size of 1 vial. 
Not all sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
AT/BE/BG/CY/EE/EL/ES/HR/HU/IE/LV/ 
LT/LU/MT/NL/RO/SI/SK 
Instituto Grifols, S.A. 
Tel: +34 93 571 01 00 
 

CZ 
Grifols S.R.O. 
Tel: +4202 2223 1415 
 

DE 
Grifols Deutschland GmbH 
Tel: +49 69 660 593 100 
 

DK/FI/IS/NO/SE 
Grifols Nordic AB 
Tel: +46 8 441 89 50 

FR 
Grifols France 
Tél: +33 (0)1 53 53 08 70 
 

IT 
Grifols Italia S.p.A. 
Tel: +39 050 8755 113 

PL 
Grifols Polska Sp. z o. o. 
Tel: +48 22 378 85 60 
 

PT 
Grifols Portugal, Lda. 
Tel: +351 219 255 200 

UK 
Grifols UK Ltd. 
Tel: +44 845 2413090 
 

 

 
This leaflet was last revised in MM/YYYY 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 
 
The following information is intended for healthcare professionals only (see section 3 for further 
information): 
 
Posology and method of administration 
 
The dose and dose regimen is dependent on the indication. 

 
The dose may need to be individualised for each patient dependent on the clinical response. Dose 
based on body weight may require adjustment in underweight or overweight patients. The following 
dosage regimens are given as a guideline. 
 



 
 
 

 - 58 - 
 

The dose recommendations are summarised in the following table: 
 

Indication Dose Frequency of injections 

Replacement therapy: 
Primary immunodeficiency syndromes 
 
 
 
 
 

Starting dose: 
0.4 - 0.8 g/kg 

 
Maintenance 
dose: 
0.2 - 0.8 g/kg 

 
 
 
 
 
every 3 - 4 weeks 

Secondary immunodeficiencies 0.2 - 0.4 g/kg every 3 - 4 weeks 
Immunomodulation: 
Primary immune thrombocytopenia  
 
 
 
 

0.8 - 1 g/kg 
 

or 
 

0.4 g/kg/d 

on day 1, possibly repeated once 
within 3 days 
 
 
for 2 - 5 days 

Guillain Barré syndrome 0.4 g/kg/d for 5 days 

Kawasaki disease 2 g/kg in one dose in association with 
acetylsalicylic acid 

Chronic inflammatory demyelinating 
polyradiculoneuropathy (CIDP) 

Starting dose: 
2 g/kg 
 
Maintenance 
dose: 
1 g/kg 

 
in divided doses over 2 - 5 days 
 
 
 
every 3 weeks over 1 - 2 days 

Multifocal motor neuropathy (MMN) Starting dose: 
2 g/kg 
 
 
Maintenance 
dose: 
1 g/kg 
 
or 
 
2 g/kg 

 
in divided doses over 
2 - 5 consecutive days 
 
 
 
every 2 - 4 weeks 
 
 
 
every 4 - 8 weeks in divided doses 
over 2 - 5 days 

 
Flebogamma DIF should be infused intravenously at an initial rate of 0.01 - 0.02 ml/kg/min for the 
first thirty minutes. If well tolerated, the rate of administration may gradually be increased to a 
maximum of 0.1 ml/kg/min. 
 
A significant increase in median platelet levels was achieved in a clinical trial in chronic ITP patients 
(64,000/µl) although it did not reach normal levels. 
 
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. 



 
 
 

 - 59 - 
 

 
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 babies and young children (aged 0 - 2 years) hereditary fructose intolerance (HFI) may not 
yet be diagnosed and may be fatal, thus, they must not receive this medicinal product. 
In persons more than 2 years old with HFI, a spontaneous aversion for fructose-containing 
foods develops and may be combined with the onset of symptoms (vomiting, gastro-intestinal 
disorders, apathy, height and weight retardation). Therefore a detailed history with regard to 
HFI symptoms has to be taken of each patient prior to receiving Flebogamma DIF.  
In case of inadvertent administration and suspicion of 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.  
 
It is strongly recommended that every time that Flebogamma DIF is administered to a patient, the 
name and batch number of the product are recorded in order to maintain a link between the patient 
and the batch of the product. 
 
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 medicinal product or waste material should be disposed of in accordance with local 
requirements. 



 
 
 

 - 60 - 
 

Package leaflet: Information for the user 
 

Flebogamma DIF 100 mg/ml solution for infusion 
Human normal immunoglobulin (IVIg) 

 
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. 
 
What is in this leaflet: 
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. How to store 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, highly purified protein extracted from 
human plasma (part of the blood of donors). This medicine belongs to 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 (2 - 18 years) who do not have sufficient antibodies 
(Flebogamma DIF is used as replacement therapy). There are two groups: 
 
• Patients with Primary Immunodeficiency Syndromes (PID), an inborn lack of antibodies 

(group 1) 
 

• Patients with Secondary Immunodeficiency Syndromes (SID) with severe or recurrent 
infections, ineffective antimicrobial treatment and either proven specific antibody failure 
(PSAF)* or serum IgG level of <4 g/l (group 2) 

 
*PSAF= failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide 
and polypeptide antigen vaccines. 
 
Treatment of adults, children and adolescents (2 - 18 years) with certain autoimmune disorders 
(immunomodulation). There are five groups: 
 
• Primary immune thrombocytopenia (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.  



 
 
 

 - 61 - 
 

 
• Guillain Barré syndrome, where the immune system damages the nerves and hinders them from 

working properly. 
 
• Kawasaki disease (in this case in conjunction with acetylsalicylic acid therapy), an illness in 

children where the blood vessels (arteries) in the body become enlarged. 
 
• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a rare and progressive 

disease causing limb weakness, numbness, pain and fatigue. 
  

• Multifocal motor neuropathy (MMN), a rare disease causing slow progressive asymmetric limb 
weakness 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 normal immunoglobulin or any of the other ingredients of this 

medicine (listed in section 6). 
 

- If you do not have enough immunoglobulins of the type IgA in your blood or have developed 
antibodies to IgA. 

 
- If you have fructose intolerance, a quite rare genetic condition where the enzyme for breaking 

down fructose is not produced. In babies and young children (aged 0 - 2 years) hereditary 
fructose intolerance may not yet be diagnosed and may be fatal, thus, they must not receive this 
medicine (see special warnings about excipients at the end of this section). 

 
Warnings and precautions  
 
Talk to your doctor, pharmacist or nurse before using Flebogamma DIF. 
 
Certain side effects may occur more frequently: 
• in case of high rate of infusion 
• 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.  
 
Patients with pre-existing risk factors 
 
Please tell your doctor if you have any other condition and/or illness, as control  is required in patients 
with pre-existing risk factors for thrombotic events (formation of blood clots inside your blood). In 
particular, tell your doctor if you have: 
• diabetes 
• high blood pressure 
• history of vascular disease or thrombosis 
• overweight  
• blood volume decrease 



 
 
 

 - 62 - 
 

• diseases which increase blood viscosity 
• age over 65 
 
Patients with a kidney problem 
 
If you have a renal disease and you are receiving Flebogamma DIF for the first time, you may suffer a 
problem in your kidneys. 
 
Your doctor will consider your risk factors and take measures such as to decrease the rate of infusion 
or to stop the treatment. 
 
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. 
 
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, 
 

• the testing of each donation and pools of plasma for signs of virus/infections, 
 
• the inclusion of 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. 
 
It is strongly recommended that every time you receive a dose of Flebogamma DIF, the name and 
batch number of the medicine (stated on the label and carton after Lot) are recorded in order to 
maintain a record of the batches used. 
 
Children and adolescents 
 
Vital signs (body temperature, blood pressure, heart rate and respiratory rate) should be observed 
during the infusion of Flebogamma DIF. 
 
Other medicines and Flebogamma DIF 
 
 Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.  
 



 
 
 

 - 63 - 
 

• Effects on vaccines: Flebogamma DIF may reduce the effectiveness of certain types of vaccines 
(live attenuated virus vaccines). In 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 
case of measles, the period is up to 1 year. 

 
 You should avoid the concomitant use of medicines that increase the excretion of water from 

your body (loop diuretics) during treatment with Flebogamma DIF. 
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, 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 (for example dizziness or nausea) during treatment, which might 
affect the ability to drive and use machines. 
 
Flebogamma DIF contains sorbitol 
 
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 persons more than 2 years old with problems to tolerate fructose, a spontaneous reaction for 
fructose-containing foods develops which may have the following symptoms: vomiting, 
gastro-intestinal disorders, apathy, height and weight retardation. Therefore, patients should be 
examined for the symptoms of Hereditary Fructose Intolerance prior to receiving 
Flebogamma DIF. 
 
Flebogamma DIF contains sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially “sodium 
free”. However, depending on the required dose, the patient may receive more than 1 vial. 
 
 
3. How to use Flebogamma DIF 
 
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 of more than 2 years old 
 
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. 
 



 
 
 

 - 64 - 
 

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 heart or 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. 
 
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, this medicine can cause side effects, although not everybody gets them. 
 
In rare and isolated cases, the following side effects have been reported with immunoglobulin 
preparations. Seek medical care with no delay 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 (which signs are rash, 

hypotension, palpitation, wheezing, coughing, sneezing and difficulty breathing among others), 
even if you have shown no hypersensitivity to previous administration. 

• Cases of temporary non-infective meningitis (which signs are headache, fear or intolerance of 
light, stiff neck). 

• Cases of temporary reduction in the number of the red cells in the blood (reversible haemolytic 
anaemia/haemolysis). 

• Cases of transient cutaneous reactions (side effects on your skin). 
• Increase in serum creatinine level (a test which measures your kidney function) and/or acute 

renal failure (which signs are low back pain, fatigue, decrease in the amount of urine). 
• Thromboembolic reactions such as myocardial infarction (tight band around the chest with 

feeling like your heart is beating too fast), stroke (muscle weakness in the face, arm, or leg, 
trouble speaking or understanding others who are speaking), pulmonary embolism (shortness of 
breath, chest pain and fatigue), deep vein thromboses (pain and swelling in an extremity). 

• Cases of transfusion related acute lung injury (TRALI) that causes hypoxia (lack of oxygen), 
dyspnoea (difficulty in breathing), tachypnoea (rapid breathing), cyanosis (lack of oxygen in 
the blood), fever and hypotension. 

 
Other side effects: 
 
Very common (may affect more than 1 in 10 infusions): 
● headache 
 
Common (may affect up to 1 in 10 infusions): 
● tachycardia (acceleration of the heart activity) 
● hypotension (low blood pressure) 
● fever (body temperature increased) 
● rigors (cold shivering sensation) or chills 
● nausea 
● vomiting 
● back pain 
● myalgia (muscle pain) 



 
 
 

 - 65 - 
 

 
Uncommon (may affect up to 1 in 100 infusions): 
● hypersensitivity 
● influenza (flu) 
● dizziness (motion sickness) 
● tremor (to tremble) 
● photophobia (excessive sensitivity to light) 
● vertigo 
● hypertension (high blood pressure) 
● wheezing 
● abdominal pain (including abdominal pain upper) 
● diarrhoea 
● flatulence 
● pruritus 
● rash 
● limb discomfort 
● muscle spasms and muscle tightness 
● neck pain 
● pain in extremity 
● chest discomfort/chest pain 
● fatigue 
● feeling cold 
● malaise 
● oedema peripheral 
● heart rate increased 
● contusion 
● urinary infection 
● meningitis aseptic (non-infective meningitis) 
● red blood cells and white blood cells decreased 
● anorexia (lack of appetite) 
● insomnia 
● 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) 
● conjunctivitis (inflammation of the conjuntiva of the eyes) 
● maculopathy (illness of the macula, in the retina of the eyes) 
● vision blurred 
● ear pain 
● cyanosis (bluish discoloration of the skin) 
● blood pressure increased or decreased 
● flushing (to blush) 
● haematoma 
● thrombosis 
● lymphoedema 
● dyspnoea (difficulty in breathing) 
● epistaxis (haemorrhage from the nose) 
● postnasal drip (excessive mucus) 
● sinus pain 
● upper-airway cough syndrome 
● abdominal discomfort and distension 
● dry mouth 
● haematemesis (vomiting blood) 
● acne 
● alopecia 



 
 
 

 - 66 - 
 

● hyperhidrosis (excessive sweating)  
● ecchymosis (large skin haematoma) 
● erythema (redness of the skin)  
● arthralgia (joint pain) 
● musculoskeletal discomfort  
● infusion related reaction and infusion site reaction (including infusion site erythema and 

infusion site pain) 
● feeling jittery (nervousness) 
● influenza like illness 
● general physical health deterioration 
● haemoglobin decreased 
● reticulocyte count increased 
● heart rate decreased 
 
Additional side effects in children and adolescents 
 
It was observed that the proportion of headache, chills, fever, nausea, vomiting, low blood pressure, 
heart rate increase and back pain in children was higher than in adults. Cyanosis (lack of oxygen in 
the blood) was reported in one child but not in adults. 
 
Side effects may be reduced by switching to Flebogamma DIF 50 mg/ml. Please consult your doctor 
should you have increased side effects. 
 
Reporting of side effects 
If you get 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 via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store 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 ºC. Do not freeze.  
 
The solution should be clear or slightly opalescent. Do not use this medicine if you notice that the 
solution is cloudy or has deposits. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
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. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 
 
 

 - 67 - 
 

Each vial of 50 ml contains: 5 g of human normal immunoglobulin 
Each vial of 100 ml contains: 10 g of human normal immunoglobulin 
Each vial of 200 ml contains: 20 g of human normal immunoglobulin 
 
The percentage of IgG subclasses is approximately 66.6% IgG1, 27.9% IgG2, 3.0% IgG3 and 
2.5% IgG4. It contains trace amounts of IgA (lower than 100 micrograms/ml). 

 
- The other ingredients are sorbitol and water for injections (see section 2 for further information 

about ingredients). 
 
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 Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
AT/BE/BG/CY/EE/EL/ES/HR/HU/IE/LV/ 
LT/LU/MT/NL/RO/SI/SK 
Instituto Grifols, S.A. 
Tel: +34 93 571 01 00 
 

CZ 
Grifols S.R.O. 
Tel: +4202 2223 1415 
 

DE 
Grifols Deutschland GmbH 
Tel: +49 69 660 593 100 
 

DK/FI/IS/NO/SE 
Grifols Nordic AB 
Tel: +46 8 441 89 50 

FR 
Grifols France 
Tél: +33 (0)1 53 53 08 70 
 

IT 
Grifols Italia S.p.A. 
Tel: +39 050 8755 113 

PL 
Grifols Polska Sp. z o. o. 
Tel: +48 22 378 85 60 
 

PT 
Grifols Portugal, Lda. 
Tel: +351 219 255 200 

UK 
Grifols UK Ltd. 
Tel: +44 845 2413090 
 

 

 
This leaflet was last revised in MM/YYYY 
 



 
 
 

 - 68 - 
 

Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 
 
The following information is intended for healthcare professionals only (see section 3 for further 
information): 
 
Posology and method of administration 
 
The dose and dose regimen is dependent on the indication. 

 
The dose may need to be individualised for each patient dependent on the clinical response. Dose 
based on body weight may require adjustment in underweight or overweight patients. The following 
dosage regimens are given as a guideline. 
 
The dose recommendations are summarised in the following table: 
 

Indication Dose Frequency of injections 

Replacement therapy: 
Primary immunodeficiency syndromes 
 
 
 
 
 

Starting dose: 
0.4 - 0.8 g/kg 
 
Maintenance 
dose: 
0.2 - 0.8 g/kg 

 
 
 
 
 
every 3 - 4 weeks  

Secondary immunodeficiencies 0.2 - 0.4 g/kg 
 

every 3 - 4 weeks 
 

Immunomodulation: 
Primary immune thrombocytopenia  
 
 
 
 

0.8 - 1 g/kg 
 
or 

 
0.4 g/kg/d 

on day 1, possibly repeated once 
within 3 days 
 
 
for 2 - 5 days 

Guillain Barré syndrome 0.4 g/kg/d for 5 days 

Kawasaki disease 2 g/kg in one dose in association with 
acetylsalicylic acid 

Chronic inflammatory demyelinating 
polyradiculoneuropathy (CIDP) 

Starting dose: 
2 g/kg 
 
Maintenance 
dose: 
1 g/kg 

 
in divided doses over 2 - 5 days 
 
 
 
every 3 weeks over 1 - 2 days 

http://www.ema.europa.eu/


 
 
 

 - 69 - 
 

Multifocal motor neuropathy (MMN) Starting dose: 
2 g/kg 
 
 
Maintenance 
dose: 
1 g/kg 
 
or 
 
2 g/kg 

 
in divided doses over 
2 - 5 consecutive days 
 
 
 
every 2 - 4 weeks 
 
 
 
every 4 - 8 weeks in divided doses 
over 2 - 5 days 

 
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 babies and young children (aged 0 - 2 years) hereditary fructose intolerance (HFI) may not 
yet be diagnosed and may be fatal, thus, they must not receive this medicinal product. 
In persons more than 2 years old with HFI, a spontaneous aversion for fructose-containing 
foods develops and may be combined with the onset of symptoms (vomiting, gastro-intestinal 
disorders, apathy, height and weight retardation). Therefore a detailed history with regard to 
HFI symptoms has to be taken of each patient prior to receiving Flebogamma DIF.  
In case of inadvertent administration and suspicion of 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.  
 



 
 
 

 - 70 - 
 

It is strongly recommended that every time that Flebogamma DIF is administered to a patient, the 
name and batch number of the product are recorded in order to maintain a link between the patient 
and the batch of the product. 
 
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 medicinal product or waste material should be disposed of in accordance with local 
requirements. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVESUBSTANCE AND MANUFACTURER RESPONSIBLE FORBATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLYAND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THEMARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TOTHE SAFE AND EFFECTIVE USE OF THE MEDICINALPRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET