Consumer medicine information

Flebogamma 5% DIF

Immunoglobulin, normal (human)

BRAND INFORMATION

Brand name

Flebogamma 5% DIF

Active ingredient

Immunoglobulin, normal (human)

Schedule

1. WHAT FLEBOGAMMA 5% DIF IS AND WHAT IT IS USED FOR

Flebogamma 5% DIF is a solution for intravenous infusion containing 50 g/l human normal immunoglobulin.

This medicine belongs to the pharmacotherapeutic group called immune sera and immunoglobulins.

Flebogamma 5% DIF is used for:

Treatment of patients who do not have sufficient antibodies (replacement therapy):

Primary immunodeficiency syndromes such as:
- congenital agammaglobulinaemia and hypogammaglobulinaemia
- common variable immunodeficiency
- severe combined immunodeficiency
- Wiskott Aldrich syndrome
Myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.
Children with congenital AIDS and recurrent infections.

Treatment of patients with certain inflammatory disorders (immunomodulation):

Idiopathic thrombocytopenic purpura (ITP), in children or adults at high risk of bleeding or prior to surgery to correct the platelet count.
Guillain Barré syndrome.

Treatment or prevention of infections after a bone marrow transplantation (allogeneic bone marrow transplantation).

If you have any question about use of Flebogamma 5% DIF please ask your doctor.

2. BEFORE YOU USE FLEBOGAMMA 5% DIF

Do not use Flebogamma 5% DIF

if you are allergic (hypersensitive) to human normal immunoglobulin or any of the other ingredients of Flebogamma 5% DIF.
(See special warnings about excipients at the end of this section).
if you have immunoglobulin A (IgA) deficiency with anti-IgA antibodies.

Take special care with Flebogamma 5% DIF

Certain adverse reactions may occur more frequently:

in case of high rate of infusion.
if you have hypo- or agammaglobulinaemia (a condition implying low immunoglobulin levels in your blood) with or without IgA deficiency.
if you are having Flebogamma 5% DIF for the first time, 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 adverse signs.

True hypersensitivity reactions are rare. They can occur in the very seldom cases of IgA deficiency with anti-IgA antibodies.

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

Patient with pre-existing risk factors

Please tell your doctor if you have any other condition and illness, as caution is required. In particular, tell your doctor if you have:

Diabetes
high blood pressure
history of vascular disease or thrombosis
overweight problem
blood volume decrease
diseases which increase blood viscosity
advanced age

Patients with a kidney problem

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

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

Special safety warning

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

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

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

It is strongly recommended that every time you receive a dose of Flebogamma 5% DIF the name and batch number of the product are recorded in order to maintain a record of the batches used.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
Effects on vaccines: Flebogamma 5% DIF may reduce the effectiveness of certain type of vaccines such as measles, rubella, mumps and varicella.

Effects on blood tests
If you are having a blood test after using Flebogamma 5% DIF, please inform the analyst or your doctor that you have taken this medicine. The level of certain antibodies can rise.

Pregnancy and breast feeding
Ask your doctor or pharmacist for advice before taking any medicine.

If you are pregnant or breast-feeding you must tell your doctor. Your doctor will decide if Flebogamma 5% DIF can be used during pregnancy and lactation.

Driving and using of machines
No effects on ability to drive and use machines have been observed.

Important information about some of the ingredients of Flebogamma 5% DIF

Special warnings about ingredients: This medicine contains 5 g of sorbitol per 100 ml as excipient. You should not use this product if you have fructose intolerance.

3. HOW TO USE FLEBOGAMMA 5% DIF

Flebogamma 5% 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 weight and will be worked out by your doctor.

At the beginning of your infusion you will receive Flebogamma 5% 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).

The solution should be clear or slightly opalescent. Do not use Flebogamma 5% DIF if you notice that the solution is cloudy or has deposits.

Flebogamma 5% DIF should not be mixed with other medicines or intravenous solutions and it should be administered by a separate intravenous line.

If you use more Flebogamma 5% DIF than you should

If you are given more Flebogamma 5% DIF than you should, tell your doctor or pharmacist immediately.

Overdose may lead to fluid overload and hyper viscosity, particularly in patients at risk, including elderly patients or patients with renal impairment.

Contact poisons information centre on 131126 for advice on management.

If you forget to use Flebogamma 5% DIF

Speak to 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.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Flebogamma 5% DIF can cause side effects, although not everybody gets them.

Tell your doctor if any of the following side effects happen during or after the infusion:

Chills
Headache
Fever
Nausea
Vomiting
Allergic reaction
Joint pain
Low blood pressure
Moderate low back pain

Rare side effects:

A sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even if you have shown no hypersensitivity to previous administration.
Cases of temporary meningitis (reversible aseptic meningitis)
Cases of temporary reduction in the number of the red cells in the blood (reversible haemolytic anaemia/haemolysis)
Cases of transient cutaneous reactions and exfoliative dermatitis
Increase in serum creatinine level and/or acute renal failure.

Very rare side effects:

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

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

5. HOW TO STORE FLEBOGAMMA 5% DIF

Keep out of the reach and sight of children.

Do not use Flebogamma 5% DIF after the expiry date which is stated on the label and carton after Exp. The expiry date refers to the last day of that month.

Store below 30 ºC. Do not freeze. Protect form light.

The product should be brought to room or body temperature before use.

The solution should be clear or slightly opalescent. Do not use Flebogamma 5% DIF if you notice that the solution is cloudy or has deposits.

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

6. FURTHER INFORMATION

What Flebogamma 5% DIF contains

The active substance is:

Human normal immunoglobulin (IVIg). One millilitre of Flebogamma 5% DIF contains 50 mg of protein, of which at least 97% is IgG.

The percentage of IgG subclasses is approximately 66.6% IgG₁, 28.5% IgG₂, 2.7% IgG₃ and 2.2% IgG₄.

Contains trace amounts of IgA (lower than 0.05 mg/ml).

The other ingredients are 5% sorbitol and water for injection.

(See section 2. ‘Before you use Flebogamma 5% DIF’ for further information about ingredients).

What Flebogamma 5% DIF looks like and contents of the pack

Flebogamma 5% DIF is a solution for infusion. The solution is clear or slightly opalescent and colourless or pale yellow.

Flebogamma 5% DIF is supplied as:

0.5 g/10 ml AUST R 140602

2.5 g/50 ml AUST R 143800

5 g/100 ml AUST R 143801

10 g/200 ml AUST R 143802

20 g/400 ml AUST R 143803

Pack size of 1 vial.

Marketing authorisation holder and manufacturer

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

Imported and distributed by:

Grifols Australia Pty Ltd
5/80 Fairbank Road,
Clayton South,
Victoria, Australia
3169

This leaflet was last approved in 23 October 2018

Published by MIMS March 2019

BRAND INFORMATION

Brand name

Flebogamma 5% DIF

Active ingredient

Immunoglobulin, normal (human)

Schedule

1 Name of Medicine

Human normal immunoglobulin.

2 Qualitative and Quantitative Composition

Flebogamma 5% DIF (dual inactivation plus nanofiltration) (IVIg) is a sterile, liquid ready to use, preparation of highly purified immunoglobulin (IgG) obtained from human plasma pools. The purification process includes cold alcohol fractionation, polyethylene glycol precipitation, ion exchange chromatography, low pH treatment, pasteurisation, solvent detergent treatment and two sequential nanofiltrations through 35 nanometre and 20 nanometre pore size nanofilters connected in series.
Flebogamma 5% DIF is a highly purified (≥ 97% IgG), unmodified, human IgG that contains the antibody specificities found in the donor population. IgG subclasses are fully represented with the following approximate percents of total IgG: IgG₁ is 66.6%, IgG₂ 28.5%, IgG₃ 2.7%, and IgG₄ 2.2%. Flebogamma 5% DIF contains only trace amounts of IgA (lower than 0.05 mg/mL).
In the final formulation, Flebogamma 5% DIF contains 5 g human normal immunoglobulin and 5 g sorbitol (as stabiliser) in 100 mL of water for injections. There is no preservative in the formulation. The Fc and Fab functions are maintained in Flebogamma 5% DIF.

3 Pharmaceutical Form

Solution for infusion.
The solution is clear or slightly opalescent, and colourless or pale yellow.
The pH of the solution ranges from 5 to 6 and the osmolality from 250 to 350 mOsm/kg, which is within the normal physiologic range.

4 Clinical Particulars

4.1 Therapeutic Indications

Flebogamma 5% DIF is indicated for:

Replacement therapy.

Primary immunodeficiency syndromes such as: congenital agammaglobulinaemia and hypogammaglobulinaemia; common variable immunodeficiency; severe combined immunodeficiency; Wiskott Aldrich syndrome.
Myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.
Children with congenital AIDS and recurrent infections.

Immunomodulation.

Idiopathic thrombocytopenic purpura (ITP), in children or adults at high risk of bleeding or prior to surgery to correct the platelet count.
Guillain Barré syndrome.

Allogeneic bone marrow transplantation.

4.2 Dose and Method of Administration

Dose.

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

Replacement therapy in primary immunodeficiency syndromes.

The dosage regimen should achieve a trough level of IgG (measured before the next infusion) of at least 4-6 g/L. Three to six months are required after the initiation of therapy for equilibration to occur. The recommended starting dose is 0.4-0.8 g/kg followed by at least 0.2 g/kg every three weeks.
The dose required to achieve a trough level of 6 g/L is of the order of 0.2-0.8 g/kg/month. The dosage interval when steady state has been reached varies from 2-4 weeks.
Trough levels should be measured in order to adjust the dose and dosage interval.

Replacement therapy in myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections; replacement therapy in children with AIDS and recurrent infections.

The recommended dose is 0.2-0.4 g/kg every three to four weeks.

Idiopathic thrombocytopenic purpura.

For the treatment of an acute episode, 0.8-1 g/kg on day one, which may be repeated once within 3 days, or 0.4 g/kg daily for two to five days. The treatment can be repeated if relapse occurs.

Guillain Barré syndrome.

0.4 g/kg/day for 3 to 7 days. Experience in children is limited.

Allogeneic bone marrow transplantation.

Human normal immunoglobulin treatment can be used as part of the conditioning regimen and after the transplant.
For the treatment of infections and prophylaxis of graft versus host disease, dosage is individually tailored. The starting dose is normally 0.5 g/kg/week, starting seven days before transplantation and for up to 3 months after transplantation.
In case of persistent lack of antibody production, dosage of 0.5 g/kg/month is recommended until antibody level returns to normal.
The dosage recommendations are summarised in Table 1.

Method of administration.

The product should be brought to room or body temperature before use.
The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits.
Flebogamma 5% 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.
This medicinal product must not be mixed with other medicinal products or intravenous fluids. It should be administered by a separate intravenous line.
Product is for single use in one patient only. Discard any residue.

4.3 Contraindications

Hypersensitivity to any of the components (see Section 4.4 Special Warnings and Precautions for Use).
Hypersensitivity to homologous immunoglobulins, especially in very rare cases of IgA deficiency, when the patient has antibodies against IgA.
Fructose intolerance (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Transmission of infectious agents.

Flebogamma 5% DIF is made from human plasma. As with all plasma derived products, the risk of transmission of infectious agents, including viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated. The risk that such products will transmit an infectious agent has been greatly reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses.
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 HIV, HBV and HCV, and for the nonenveloped viruses HAV and parvovirus B19.
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 Flebogamma 5% 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.

Special warnings about excipients.

This medicinal product contains 50 mg of sorbitol per mL as excipient. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Special precautions should be taken with babies and young children because this fructose intolerance may not yet be diagnosed and may be fatal. Interferences with determination of blood glucose levels are not expected.

Infusion/ administration.

Certain severe adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given (see Section 4.2 Dose and Method of Administration) must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period.
Certain adverse reactions may occur more frequently:
in case of high rate of infusion;
in patients with hypo- or agammaglobulinaemia with or without IgA deficiency;
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.
True hypersensitivity reactions are rare. They can occur in the very seldom cases of IgA deficiency with anti-IgA antibodies.
Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.
Potential complications can often be avoided by ensuring:
that patients are not sensitive to human normal immunoglobulin by first injecting the product slowly at an initial rate of 0.01-0.02 mL/kg/min;
that patients 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 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.

Association with thromboembolic phenomenon.

There is clinical evidence of an association between IVIg administration and thromboembolic events such as myocardial infarction, 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 hypovolemic patients, and patients with diseases which increase blood viscosity).

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, hypovolemia, overweight, concomitant nephrotoxic medicinal products or age over 65.
In case of renal impairment, IVIg discontinuation should be considered.
While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIg products, 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 sucrose may be considered.
In patients at risk for acute renal failure or thromboembolic adverse reactions, IVIg products should be administered at the minimum rate of infusion and dose practicable.
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.
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 side effect.
In case of shock, standard medical treatment for shock should be implemented.

Use in the elderly.

No data available.

Paediatric use.

It is recommended to monitor vital signs when administering Flebogamma 5% DIF to paediatric patients.

Effects on laboratory tests.

Interference with serological testing.

After injection 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 antiglobulin test (Coomb's test).

4.5 Interactions with Other Medicines and Other Forms of Interactions

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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No fertility effects have been conducted in animals on Flebogamma 5% DIF.
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. 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.
Immunoglobulins are excreted in breast milk. The safety of this product for use during lactation has not been established in controlled clinical trials. Flebogamma 5% DIF should, therefore, only be given with caution to breastfeeding mothers.

4.7 Effects on Ability to Drive and Use Machines

No effects on ability to drive and use machines have been observed.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions such as chills, headache, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally.
Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.
Cases of reversible aseptic meningitis, isolated cases of reversible haemolytic anaemia/haemolysis and rare cases of transient cutaneous reactions and exfoliative dermatitis, have been observed with human normal immunoglobulin.
Increase in serum creatinine level and/or acute renal failure have been observed.
Very rarely: thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses.
Two multicenter clinical trials were performed, one of them in children (n = 3) and adults with primary immune deficiency and the second one in patients with chronic immune thrombocytopenic purpura in acute phase. Forty six patients were included in the first trial and 41 completed the study. They were followed during 1 year of treatment at a dose of 300-600 mg/kg every 3 to 4 weeks. A total of 20 patients were included in the second study. Patients received a total dose of 400 mg/kg body weight for 5 consecutive days and were followed for 3 months. Therefore, a total of 66 patients have been exposed to Flebogamma 5% DIF and they have received 806 infusions. Data from both studies indicate a good tolerability of the product as incidence of adverse events was low and most of them were mild to moderate in intensity.
Of the 806 infusions administered in patients enrolled in both studies 10.8% (1 sided 95% CI upper bound = 12.9%) were associated with an adverse event suspected to be related to the product. No patients died, only 6 patients withdrew from the studies but none of them because of potentially related adverse events. Four patients experienced 8 serious adverse events that were considered not related to the study medicinal product. Pyrexia and headache were the most frequently reported adverse events potentially related to the medicinal product in both studies.
The adverse drug reactions reported in the 2 trials by at least the 5% of the patients are summarised and categorised according to the MedDRA system organ class in Table 2.
Frequency has been determined using the following criteria: 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, undesirable effects are presented in order of decreasing of seriousness.
For safety with respect to transmissible agents, see Section 4.4 Special Warnings and Precautions for Use.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdose may lead to fluid overload and hyper viscosity, particularly in patients at risk, including elderly patients or patients with renal impairment.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

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.

Clinical trials.

One multicenter clinical trial was performed in children (n = 3) and adults with primary immune deficiency. Forty six patients were included and 41 completed the study (15-75 years; 29 males). They were followed during 1 year of treatment at a dose of 300-600 mg/kg every 3 to 4 weeks. The results showed that subjects had a serious acute bacterial infection rate of 0.021 infections/subject/year (98% CI = 0.001 to 0.112). The annualized mean number of days of work/ school missed was 12.95 ± 40 and the annualized mean number of days of hospitalization was 0.77 ± 3.5.
One multicenter clinical trial was performed in patients with chronic immune thrombocytopenic purpura in acute phase (platelet count < 20 x 10⁹/L). A total of 19 patients with ITP were included (age: 18-85 years; 13 females). Patients received a total dose of 400 mg/kg body weight for 5 consecutive days and were followed for 3 months. Fourteen (14) patients presented a response (platelet count ≥ 50 x 10⁹/L) being the rate of responders as 14/19 (74%). The platelet counts was ≥ 50 x 10⁹/L by day 5 and the duration of response had a mean result of > 14.3 ± 24 days (median of ≥ 7, range 1-92 days) estimated from the first measurement that the subject had a platelet count greater than or equal to 50 x 10⁹/L to the last measurement that the subject had still a platelet count over that level. A total of 18/19 (95%) patients had a regression of bleedings on day 10 and 17/19 (89%) on day 14 after treatment.

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.
One multicenter trial to determine the clinical efficacy, pharmacokinetics and safety was performed in 46 patients with primary immunodeficiency. Trough IgG levels and other standard pharmacokinetic parameters such as serum C_max, AUC, half-life, clearance and volume of distribution for total IgG and subclass IgG were determined in a subgroup of 20 patients (17-75 years; 11 female). Mean trough IgG level ranged from 773 to 1143 mg/dL for 21 day infusion schedule patients and from 777 to 1137 mg/dL for 28 day infusion schedule patients. The mean serum half-life for total IgG was 30 and 32 days for the 21 and 28 day dosing schedule, respectively, and the mean clearances were 139 and 109 mL/day. For IgG subclasses the mean serum half-life ranged from 26 to 40 days. For both dosing schedules, the mean AUC levels for the total IgG was around 32,000 day.mg/dL, the mean C_max levels was around 2000 mg/dL, and the mean volume of distribution between 4.9 and 5.5 L.
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.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies have been conducted with Flebogamma 5% DIF.

Carcinogenicity.

No carcinogenicity studies have been conducted with Flebogamma 5% DIF.

6 Pharmaceutical Particulars

6.1 List of Excipients

D-sorbitol, water for injections.
Flebogamma 5% DIF contains 5 g sorbitol (as stabiliser) in 100 mL of water for injections.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

2 years.

6.4 Special Precautions for Storage

Store below 30°C. Do not freeze. Protect from light.
Contains no antimicrobial preservative. Use in one patient on one occasion only.
Do not use after expiry date.

6.5 Nature and Contents of Container

Flebogamma 5% DIF is a solution for infusion supplied in a type II glass vial closed with a chloro-butyl-rubber stopper.
Flebogamma 5% 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.
Pack size: 1 vial.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

The product should be brought to room or body temperature before use.
The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

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Flebogamma 5% DIF

Immunoglobulin, normal (human)

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