FLEBOGAMMA DIF 50mg / ml infusion solution medication leaflet

Flebogamma DIF 50 mg/ml solution for infusion

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%

Minimum level anti-measles IgG is 4.5 IU/ml.

The maximum IgA content is 50 micrograms/ml.

Produced from the plasma of human donors.

One ml contains 50 mg of D-sorbitol.

For the full list of excipients, see section 6.1.

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.

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)* orserum 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 polysaccharideand polypeptide antigen vaccines

Measles pre-/post exposure prophylaxis for susceptible adults, children and adolescents (2 - 18 years)in whom active immunisation is contraindicated or not advised.

Consideration should also be given to official recommendations on intravenous humanimmunoglobulin use in measles pre-/post exposure prophylaxis and active immunisation.

Immunomodulation in adults, children and adolescents (2 - 18 years) in:

- Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgeryto 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)

IVIg therapy should be initiated and monitored under the supervision of a physician experienced in thetreatment of immune system disorders.

The dose and dose regimen are dependent on the indication.

The dose may need to be individualised for each patient dependent on the clinical response. Dosebased on body weight may require adjustment in underweight or overweight patients.

The following dose regimens are given as a guidance.

Replacement therapy in primary immunodeficiency syndromes

The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least6 g/l or within the normal reference range for the population age. 3 - 6 months are required after theinitiation of therapy for equilibration (steady-state IgG levels) to occur. The recommended startingdose is 0.4 - 0.8 g/kg given once followed by at least 0.2 g/kg given every 3 - 4 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. Thedosage 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. Toreduce the rate of bacterial infections, it may be necessary to increase the dosage and aim for highertrough levels.

Replacement therapy in secondary immunodeficiencies (as defined in 4.1)

The recommended dose is 0.2 - 0.4 g/kg every 3 - 4 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

- 3 -may be necessary in patients with persisting infection; a dose decrease can be considered when thepatient remains infection free.

Measles pre-/post exposure prophylaxis

If a susceptible patient has been exposed to measles, a dose of 0.4 g/kg given as soon as possible andwithin 6 days of exposure should provide a serum level > 240 mIU/ml of measles antibodies for atleast 2 weeks. Serum levels should be checked after 2 weeks and documented. A further dose of0.4 g/kg possibly to be repeated once after 2 weeks may be necessary to maintain the serum level> 240 mIU/ml.

If a PID/SID patient has been exposed to measles and regularly receives IVIg infusions, it should beconsidered to administer an extra dose of IVIg as soon as possible and within 6 days of exposure. Adose of 0.4 g/kg should provide a serum level > 240 mIU/ml of measles antibodies for at least2 weeks.

If a PID/SID patient is at risk of future measles exposure and receives a IVIg maintenance dose of lessthan 0.53 g/kg every 3 - 4 weeks, this dose should be increased once to 0.53 g/kg. This should providea serum level of >240 mIU/ml of measles antibodies for at least 22 days after infusion.

Immunomodulation in:

Primary immune thrombocytopenia

There are two alternative treatment schedules:

* 0.8 - 1 g/kg given on day 1; this dose may be repeated once within 3 days.

* 0.4 g/kg given daily for 2 - 5 days. The treatment can be repeated if relapse occurs.

Guillain Barré syndrome0.4 g/kg/day over 5 days (possible repeat of dosing in case of relapse).

Kawasaki disease2.0 g/kg should be administered as a single dose. Patients should receive concomitant treatment withacetylsalicylic 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 physician’s discretion basedupon the patient response and maintenance response. The dosing and intervals may have to be adaptedaccording 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.

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If the treatment is effective, long-term treatment should be subject to the physician’s discretion basedupon the patient response and maintenance response. The dosing and intervals may have to be adaptedaccording to the individual course of the disease.

The dose recommendations are summarised in the following table:

Indication Dose Frequency of infusions

Replacement therapy:

Primary immunodeficiency syndromes Starting dose:

0.4 - 0.8 g/kg

0.2 - 0.8 g/kg every 3 - 4 weeks

Secondary immunodeficiencies (as defined 0.2 - 0.4 g/kg every 3 - 4 weeksin 4.1)

Measles pre/post exposure prophylaxis:

Post-exposure prophylaxis in susceptible 0.4 g/kg As soon as possible and withinpatients 6 days, possibly to be repeated onceafter 2 weeks to maintain themeasles antibody serum level> 240 mIU/ml

Post-exposure prophylaxis in PID/SID 0.4 g/kg In addition to maintenance therapy,patients given as an extra dose within 6 daysof exposure

Pre-exposure prophylaxis in PID/SID 0.53 g/kg If a patient receives a maintenancepatients dose of less than 0.53 g/kg every3 - 4 weeks, this dose should beincreased once to at least 0.53 g/kg

Immunomodulation:

Primary immune thrombocytopenia 0.8 - 1 g/kg on day 1, possibly repeated oncewithin 3 daysor0.4 g/kg/d 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 withacetylsalicylic acid

Chronic inflammatory demyelinating Starting dose:

polyradiculoneuropathy (CIDP) 2 g/kg in divided doses over 2 - 5 days

1 g/kg every 3 weeks in divided doses over1 - 2 days

Multifocal motor neuropathy (MMN) Starting dose:2 g/kg in divided doses over2 - 5 consecutive days

Maintenance dose:1 g/kg every 2 - 4 weeksor2 g/kg every 4 - 8 weeks in divided dosesover 2 - 5 days

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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 theposology for each indication is given by body weight and must be adjusted to the clinical outcome ofthe above-mentioned conditions.

No evidence is available to require a dose adjustment.

No dose adjustment unless clinically warranted, see section 4.4.

No dose adjustment unless clinically warranted, see section 4.4.

For intravenous use.

Flebogamma DIF 50 mg/ml should be infused intravenously at an initial rate of0.01 - 0.02 ml/kg/min for the first thirty minutes. See section 4.4. In case of adverse reaction, eitherthe rate of administration must be reduced or the infusion stopped. If well tolerated, the rate ofadministration may gradually be increased to a maximum of 0.1 ml/kg/min.

Hypersensitivity to the active substance (human immunoglobulins) or to any of the excipients (seesections 4.4 and 6.1).

Hereditary fructose intolerance (see section 4.4).

In babies and young children (aged 0 - 2 years) hereditary fructose intolerance (HFI) may not yet bediagnosed 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.

Sorbitol

Patients with rare hereditary fructose intolerance (HFI) must not be given this medicine unlessstrictly necessary.

Babies and young children (below 2 years of age) may not yet be diagnosed with hereditaryfructose intolerance (HFI). Medicines (containing sorbitol/fructose) given intravenously may belife-threatening and should be contraindicated in this population unless there is anoverwhelming clinical need and no alternatives are available.

A detailed history with regard to HFI symptoms has to be taken of each patient prior to beinggiven this medicinal product.

In order to improve the traceability of biological medicinal products, the name and the batchnumber of the administered product should be clearly recorded.

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Precautions for use

Potential complications can often be avoided by ensuring that patients:

- are not sensitive to human normal immunoglobulin by initially administering 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, patientsnaive to human normal immunoglobulin, patients switched from an alternative IVIg product orwhen there has been a long interval since the previous infusion should be monitored during thefirst infusion and for the first hour after the first infusion in a controlled healthcare setting inorder to detect potential adverse signs and to ensure that emergency treatment can beadministered immediately should problems occur. All other patients should be observed for atleast 20 minutes after administration

In all patients, IVIg administration requires:

- adequate hydration prior to the initiation of the IVIg infusion

- 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 infusion rate must be reduced or the infusion stopped. Thetreatment required depends on the nature and severity of the adverse reaction.

Infusion-related reaction

Certain adverse reactions (e.g. headache, flushing, chills, myalgia, wheezing, tachycardia, lower backpain, nausea, and hypotension) may be related to the rate of infusion. The recommended infusion rategiven under section 4.2 must be closely followed. Patients must be closely monitored and carefullyobserved 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, whenthe human normal immunoglobulin product is switched or when there has been a long intervalsince the previous infusion

- in patients with an active infection or underlying chronic inflammation

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 eventssuch as myocardial infarction, cerebral vascular accident (including stroke), pulmonary embolism anddeep vein thromboses which is assumed to be related to a relative increase in blood viscosity throughthe high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing andinfusing 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 thromboticepisodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periodsof immobilisation, severely hypovolaemic patients, and patients with diseases which increase bloodviscosity).

In patients at risk for thromboembolic adverse reactions, IVIg products should be administered at theminimum rate of infusion and dose practicable.

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Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, riskfactors 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 apotential increased risk for developing acute renal failure, and again at appropriate intervals. In patientsat risk for acute renal failure, IVIg products should be administered at the minimum rate of infusionand 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 manyof 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. Inpatients 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)

AMS has been reported to occur in association with IVIg treatment. The syndrome usually beginswithin several hours to 2 days following IVIg treatment. Cerebrospinal fluid (CSF) studies arefrequently positive with pleocytosis up to several thousand cells per mm3, predominantly from thegranulocytic series, and elevated protein levels up to several hundred mg/dl. AMS may occur morefrequently in association with high-dose (2 g/kg) IVIg treatment.

Patients exhibiting such signs and symptoms should receive a thorough neurologicalexamination, including CSF studies, to rule out other causes of meningitis.

Discontinuation of IVIg treatment has resulted in remission of AMS within several days withoutsequelae.

Haemolytic anaemia

IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivocoating of red blood cells (RBC) with immunoglobulin, causing a positive direct antiglobulin reaction(Coombs’ test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapydue to enhanced RBC sequestration. IVIg recipients should be monitored for clinical signs andsymptoms of haemolysis. (See section 4.8.).

Neutropenia/Leukopenia

A transient decrease in neutrophil count and/or episodes of neutropenia, sometimes severe, have beenreported after treatment with IVIg. This typically occurs within hours or days after IVIg administrationand 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 duringor within 6 hours after a transfusion, often within 1 - 2 hours. Therefore, IVIg recipients must bemonitored 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.

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Interference with serological testing

After the administration of immunoglobulin the transitory rise of the various passively transferredantibodies 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 someserological 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 fromhuman blood or plasma include selection of donors, screening of individual donations and plasmapools for specific markers of infection and the inclusion of effective manufacturing steps for theinactivation/removal of viruses. Despite this, when medicinal products prepared from human blood orplasma 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 immunodeficiencyvirus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-envelopedhepatitis A and parvovirus B19 viruses.

There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19transmission with immunoglobulins and it is also assumed that the antibody content makes animportant contribution to viral safety.

It is strongly recommended that every time that Flebogamma DIF is administered to a patient, thename and batch number of the product are recorded in order to maintain a link between the patient andthe batch of the product.

This medicinal product contains less than 7.35 mg sodium per 100 ml, equivalent to 0.37% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

It is recommended to monitor vital signs when administering Flebogamma DIF to paediatric patients.

Live attenuated virus vaccines

Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months theefficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. Afteradministration of this medicinal product, an interval of 3 months should elapse before vaccination withlive 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

It is expected that the same interactions than those mentioned for the adults may be presented by thepaediatric population.

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The safety of this medicinal product for use in human pregnancy has not been established in controlledclinical trials and therefore should only be given with caution to pregnant women. IVIg products havebeen shown to cross the placenta, increasingly during the third trimester.

Clinical experience with immunoglobulins suggests that no harmful effects on the course ofpregnancy, or on the foetus and the neonate are expected.

The safety of this medicinal product for use in breast-feeding mothers has not been established incontrolled clinical trials and therefore should only be given with caution to breast-feeding mothers.

Immunoglobulins are excreted into human milk. No negative effects on the breastfed newborns/infantsare anticipated.

Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to beexpected.

The ability to drive and operate machines may be impaired by some adverse reactions, such asdizziness, associated with Flebogamma DIF. Patients who experience adverse reactions duringtreatment should wait for these to resolve before driving or operating machines.

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 bloodpressure 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 thepatient has shown no hypersensitivity to previous administration

* (rarely) transient cutaneous reactions (including cutaneous lupus erythematosus - frequencyunknown)

* (very rarely) thromboembolic reactions such as myocardial infarction, stroke, pulmonaryembolism, 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.

The table presented below is according to the MedDRA system organ classification (SOC and

Preferred Term Level).

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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 totalof 128 patients exposed to Flebogamma DIF 50 mg/ml (with a total of 1318 infusions)

Frequency Frequency

MedDRA System Organ

Adverse reaction per per

Class (SOC)patient infusion

Infections and infestations Nasopharyngitis Uncommon Uncommon

Immune system disorders Hypersensitivity Uncommon Rare

Psychiatric disorders Abnormal behaviour Uncommon Rare

Migraine Uncommon Rare

Nervous system disorders Headache Very Common Common

Dizziness Common Uncommon

Tachycardia Common Common

Cardiovascular disorder Uncommon Rare

Hypertension Common Uncommon

Diastolic hypertension Common Uncommon

Systolic hypertension Uncommon Uncommon

Vascular disorders Hypotension Common Common

Diastolic hypotension Common Common

Blood pressure fluctuation Uncommon Rare

Flushing Uncommon Rare

Bronchitis Common Uncommon

Dyspnoea Uncommon Rare

Asthma Uncommon Rare

Epistaxis Uncommon Rare

Respiratory, thoracic and

Productive cough Uncommon Uncommonmediastinal disorders

Cough Uncommon Rare

Wheezing Common Uncommon

Laryngeal pain Uncommon Rare

Nasal discomfort Uncommon Rare

Diarrhoea Common Uncommon

Vomiting Common Uncommon

Gastrointestinal disorders Abdominal pain upper Common Uncommon

Abdominal pain Common Uncommon

Nausea Common Uncommon

Rash pruritic Uncommon Uncommon

Dermatitis contact Uncommon Rare

Skin and subcutaneous tissue Urticaria Common Uncommondisorders Pruritus Uncommon Uncommon

Rash Uncommon Rare

Hyperhidrosis Uncommon Rare

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Frequency Frequency

MedDRA System Organ

Adverse reaction per per

Class (SOC)patient infusion

Arthralgia Common Uncommon

Myalgia Common Uncommon

Musculoskeletal and Back pain Common Uncommonconnective tissue disorders Neck pain Uncommon Rare

Pain in extremity Uncommon Rare

Muscle spasms Uncommon Rare

Renal and urinary disorders Urinary retention Uncommon Rare

Pyrexia Very Common Common

Chest pain Uncommon Rare

Oedema peripheral Uncommon Rare

Chills Common Uncommon

Rigors Common Uncommon

Pain Common Uncommon

Asthenia Uncommon Rare

General disorders and Injection site reaction Common Uncommonadministration site conditions Infusion site erythema Uncommon Rare

Infusion site extravasation Uncommon Rare

Injection site pruritus Uncommon Rare

Infusion site inflammation Uncommon Rare

Injection site swelling Uncommon Rare

Injection site oedema Uncommon Rare

Infusion site pain Uncommon Rare

Injection site pain Uncommon Rare

Blood pressure increased Uncommon Rare

Blood pressure systolic increased Common Uncommon

Blood pressure systolic decreased Uncommon Uncommon

Body temperature increased Common Uncommon

Alanine aminotransferase increased Uncommon Rare

Coombs test positive Common Uncommon

Injury, poisoning and

Infusion related reaction Uncommon Uncommonprocedural complications

The most reported post-marketing ADRs received since the product was authorised for bothconcentrations were chest pain, flushing, blood pressure increased and decreased, malaise, dyspnoea,nausea, vomiting, pyrexia, back pain, headache and chills.

The safety results for 29 paediatric patients (those  17 years old) included in the PID studies wereevaluated. It was observed that the proportion of headache, pyrexia, tachycardia and hypotension inchildren was higher than in adults. Assessment of vital signs in clinical trials of the paediatricpopulation did not indicate any pattern of clinically relevant changes.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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Overdose may lead to fluid overload and hyperviscosity, particularly in patients at risk, includinginfants, elderly patients or patients with cardiac or renal impairment (see section 4.4).

Information on overdose in children has not been established with Flebogamma DIF. However, as inadult population, overdose may lead to fluid overload and hyperviscosity as with any other intravenousimmunoglobulins.

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 ofantibodies against infectious agents.

Human normal immunoglobulin contains the IgG antibodies present in the normal population. It isusually prepared from pooled plasma from not fewer than 1000 donors. It has a distribution ofimmunoglobulin G subclasses closely proportional to that in native human plasma.

Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to thenormal range.

The mechanism of action in indications other than replacement therapy is not fully elucidated, butincludes immunomodulatory effects. A significant increase in median platelet levels was achieved in aclinical 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 patientswith primary immunodeficiency (one in both adults and in children above 10 years and another inchildren between 2 to 16 years) and another for immunomodulation in adult patients with immunethrombocytopenic purpura.

Human normal immunoglobulin is immediately and completely bioavailable in the recipient’scirculation after intravenous administration.

It is distributed relatively rapidly between plasma and extravascular fluid, after approximately3 - 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 patientto patient, in particular in primary immunodeficiency.

IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.

No differences of the pharmacokinetic properties are expected in the paediatric population.

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Measles pre-/post exposure prophylaxis (see references)

No clinical studies have been performed in susceptible patients regarding Measles pre-/post exposureprophylaxis.

Flebogamma DIF 50mg/ml meets the minimum measles antibody potency specification threshold of0.36 x Center for Biologics Evaluation and Research (CBER) Standard. The dosing is based onpharmacokinetic calculations which take body weight, blood volume and half-life of immunoglobulinsinto consideration. These calculations predict a:

▪ Serum titer at 13.5 days = 270 mIU/ml (dose: 0.4 g/kg) This provides a safety margin more thandouble that of the WHO protective titer of 120 mIU/ml▪ Serum titer at 22 days (t1/2) = 180 mIU/ml (dose: 0.4 g/kg)▪ Serum titer at 22 days (t1/2) = 238.5 mIU/ml (dose: 0.53 g/kg -pre-exposure prophylaxis)

Single dose toxicity studies were carried out in rats and mice. The absence of mortality in thenon-clinical studies performed with Flebogamma DIF with doses up to 2500 mg/kg, and the lack ofany confirmed relevant adverse sign affecting respiratory, circulatory and central nervous system ofthe 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 havenot been studied.

D-sorbitol

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts, nor with any other IVIg products.

2 years.

Do not store above 30 ºC.

Do not freeze.

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.

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

The solution should be clear or slightly opalescent and colourless or pale yellow. Solutions that arecloudy or have deposits should not be used.

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

Instituto Grifols, S.A.

Can Guasc, 2 - Parets del Vallès08150 Barcelona - Spain

EU/1/07/404/001-005

Date of first authorisation: 23 August 2007

Date of latest renewal: 24 April 2017

MM/YYYY

Detailed information on this product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu.

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