Consumer medicine information

Flebogamma 10% DIF

Immunoglobulin, normal (human)

BRAND INFORMATION

Brand name

Flebogamma 10% DIF

Active ingredient

Immunoglobulin, normal (human)

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Flebogamma 10% DIF.

1. WHAT FLEBOGAMMA 10% DIF IS AND WHAT IT IS USED FOR

What Flebogamma 10% DIF is

Flebogamma 10% DIF is a solution for intravenous infusion containing 100 g/l human normal immunoglobulin.

Flebogamma 10% DIF is one of the group of medicines called intravenous immunoglobulins. These are used to treat conditions where the body’s defence system against disease is not working properly.

What Flebogamma 10% DIF is used for

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

  • Primary Immunodeficiency (PI) Diseases
  • Symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.

Treatment of patients with certain inflammatory disorders (immunomodulation):

  • Idiopathic Thrombocytopaenic Purpura (ITP), in children or adults at high risk of bleeding or prior to surgery to correct the platelet count.
  • Guillain Barré syndrome.
  • It is used to treat Kawasaki disease, an illness in children where the blood vessels (arteries) in the body become enlarged.

If you have any question about use of Flebogamma 10% DIF please ask your doctor.

2. BEFORE YOU USE FLEBOGAMMA 10% DIF

Do not use Flebogamma 10% DIF

  • If you are allergic (hypersensitive) to human normal immunoglobulin or any of the other ingredients of Flebogamma 10% DIF (see special warnings about excipients at the end of this section).
  • If you do not have enough immunoglobulins of the type IgA in your blood or have developed antibodies to IgA.
  • If you have hereditary fructose intolerance, a quite rare genetic condition where the enzyme for breaking down fructose is not produced.

Take special care with Flebogamma 10% 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 10% 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 adverse signs.

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

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

Patient with pre-existing risk factors

Please tell your doctor if you have any other condition and/or illness, as caution is required in patients with pre-existing risk factors for clotting (thrombotic) events. 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 10% 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 10% DIF may reduce the effectiveness of certain type of vaccines such as measles, rubella, mumps and varicella.

Effects on blood tests
After receiving Flebogamma 10% 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 10% DIF, please tell the analyst or your doctor that you have been given this medicine.

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 10% DIF can be used during pregnancy and breast-feeding.

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

Important information about some of the ingredients of Flebogamma 10% DIF

Special warnings about ingredients: This medicine contains 5 g of sorbitol per 100 ml as excipient. If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before taking this medicine. You should not use this product if you have fructose intolerance. In babies and young children hereditary fructose intolerance may not yet be diagnosed and may be fatal, thus, they should not receive this medicine.

3. HOW TO USE FLEBOGAMMA 10% DIF

Flebogamma 10% 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.

At the beginning of your infusion you will receive Flebogamma 10% DIF at a slow rate (0.01 ml/kg/min (1 mg/kg/min)). Depending on how comfortable you feel, your doctor may then gradually increase the infusion rate (up to 0.08 ml/kg/min (8 mg/kg/min)).

The solution should be clear or slightly opalescent. Do not use Flebogamma 10% DIF if you notice that the solution is cloudy or has deposits.

Flebogamma 10% DIF should not be mixed with other medicines or intravenous solutions and it should be administered by a separate intravenous line.

Use in children

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

If you use more Flebogamma 10% DIF than you should

If you are given more Flebogamma 10% DIF than you should, your body may take on too much fluid. You may have fatigue, difficult breathing, swelling in the legs and arms, increase in weight or sleeping difficulties. This could particularly happen when you are a patient at risk, e.g. an elderly patient or a patient having problems with your kidneys. Tell your doctor or pharmacist immediately.

Contact poisons information centre on 131126 for advice on management.

If you forget to use Flebogamma 10% 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.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Flebogamma 10% DIF can cause side effects, although not everybody gets them.

In rare and isolated cases, the following side effects have been reported with immunoglobulin preparations. Tell your doctor if any of the following side effects happen during or after the infusion:

  • Allergic reactions and isolated cases of 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.
  • Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses.

Three clinical studies with Flebogamma 10% DIF were conducted. In these studies different side effects have been observed. These side effects and frequency are detailed below using the following convention:

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

Very common:

  • headache
  • nausea
  • fever (body temperature increased)

Common:

  • red blood cells and white blood cells decreased
  • heart rate increase or tachycardia (acceleration of the heart activity)
  • cyanosis
  • vertigo
  • photophobia (excessive sensitivity to light)
  • abdominal pain (including abdominal pain upper)
  • diarrhoea
  • vomiting
  • infusion related reaction and infusion site reaction
  • infusion site pain
  • pain
  • rigors (cold shivering sensation)
  • tremor/chills (to tremble)
  • influenza like illness
  • chest discomfort
  • feeling cold
  • edema peripheral (swelling of extremities due to the accumulation of fluids)
  • blood pressure decrease
  • blood pressure increase
  • haemoglobin decreased (haemoglobin is a substance in the blood which carries oxygen)
  • anorexia (lack of appetite)
  • myalgia (muscle pain)
  • muscle tightness
  • back pain
  • dizziness (motion sickness)
  • radicular syndrome (neck or back pain and other symptoms such as numbness, tingling and weakness in the arms or legs)
  • epistaxis
  • ecchymosis (large skin hematoma)
  • erythema (redness of the skin)
  • pruritus (itching)
  • rash (eruption of the skin)
  • flushing (to blush)
  • thrombosis

Uncommon:

  • ear pain
  • conjunctivitis (inflammation of the conjuntiva of the eyes)
  • maculopathy (illness of the macula, in the retina of the eyes)
  • abdominal distension
  • flatulence
  • chest pain
  • fatigue
  • feeling jittery (nervousness)
  • infusion site erythema (redness in the area of injection)
  • malaise
  • influenza (flu)
  • urinary infection
  • arthralgia (joint pain)
  • muscle spasms
  • neck pain
  • pain in extremities
  • syncope vasovagal (fainting)
  • postnasal drip (excessive mucus)
  • sinus pain
  • wheezing
  • acne
  • haematoma

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 10% DIF

Keep out of the reach and sight of children.

Do not use Flebogamma 10% 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 10% 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 10% DIF contains

  • The active substance is human normal immunoglobulin (IVIg). One ml contains 100 mg of human normal immunoglobulin, of which at least 97% is IgG.
    One vial of 50 ml contains: 5 g of human normal immunoglobulin
    One vial of 100 ml contains: 10 g of human normal immunoglobulin
    One vial of 200 ml contains: 20 g of human normal immunoglobulin
    The percentage of IgG subclasses is approximately 66.6% IgG1, 27.9% IgG2, 3.0% IgG3 and 2.5% IgG4.Contains trace amounts of IgA (lower than 100 micrograms/ml).
  • The other ingredients are 5% sorbitol and water for injection. (see section 2 for further information about ingredients).

What Flebogamma 10% DIF looks like and contents of the pack

Flebogamma 10% DIF is a solution for infusion. The solution is clear or slightly opalescent and colourless or pale yellow.

Flebogamma 10% DIF is supplied as:

5 g/50 ml AUST R 184353

10 g/100 ml AUST R 182358

20 g/200 ml AUST R 182359

Pack size of 1 vial.

Not all sizes may be marketed.

Marketing authorisation holder and manufacturer

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

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 10% DIF

Active ingredient

Immunoglobulin, normal (human)

Schedule

S4

 

1 Name of Medicine

Human normal immunoglobulin.

2 Qualitative and Quantitative Composition

Flebogamma 10% 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 10% 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, 27.9%, IgG3, 3.0%, and IgG4, 2.5%. Flebogamma 10% DIF contains only trace amounts of IgA (lower than 100 microgram/mL).
In the final formulation, Flebogamma 10% DIF contains 10 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 10% 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

Replacement therapy indications.

Primary immunodeficiency (PI) diseases.
Symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.

Immunomodulation indications.

Idiopathic thrombocytopaenic purpura (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count.
Guillain Barré syndrome.
Kawasaki disease.

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 indications.

Primary immunodeficiency (PI) diseases.

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.

Symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.

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

Idiopathic thrombocytopenic purpura.

The clinical trials performed with the product included patients with chronic idiopathic thrombocytopenic purpura in an acute episode. 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.
The product has not been studied in patients diagnosed of acute idiopathic thrombocytopenic purpura

Guillain Barré syndrome.

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

Kawasaki disease.

1.6-2.0 g/kg should be administered in divided doses over two to five days or 2.0 g/kg as a single dose. Patients should receive concomitant treatment with acetylsalicylic acid.
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 10% DIF should be infused intravenously at an initial rate of 0.01 mL/kg/min (1 mg/kg/min) for the first thirty minutes. If tolerated, advance to 0.02 mL/kg/min (2 mg/kg/min) for the second 30 minutes. Again, if tolerated, advance to 0.04 mL/kg/min (4 mg/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 (8 mg/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 Special Warnings and Precautions for Use).
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 the active substance or to any of the excipients (see Section 4.4 Special Warnings and Precautions for Use).
Hypersensitivity to human immunoglobulins, especially in very rare cases of IgA deficiency, when the patient has antibodies against IgA.
Hereditary fructose intolerance. In babies and young children hereditary fructose intolerance may not yet be diagnosed and may be fatal, thus, they should not receive this medicinal product.

4.4 Special Warnings and Precautions for Use

An apparent increase in the rate of adverse events was observed in clinical trials with Flebogamma 10% DIF compared to Flebogamma 5% DIF.
Flebogamma 10% DIF should be infused intravenously at an initial rate of 0.01 mL/kg/min (1 mg/kg/min) for the first thirty minutes. If tolerated, advance to 0.02 mL/kg/min (2 mg/kg/min) for the second 30 minutes. Again, if tolerated, advance to 0.04 mL/kg/min (4 mg/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 (8 mg/kg/min).

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 reactions to the medicinal product 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.
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 mL/kg/min (1 mg/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 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 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 reactions.
In case of shock, standard medical treatment for shock should be implemented.
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.

Hypersensitivity.

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.

Thromboembolism.

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).
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, 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 an excipient 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. Flebogamma DIF does not contain sucrose.
In patients at risk for acute renal failure, IVIg products should be administered at the minimum rate of infusion and dose practicable.

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.

Transfusion related acute lung injury (TRALI).

Noncardiogenic pulmonary edema may occur in patients following Flebogamma 10% DIF treatment. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment.
Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of antineutrophil antibodies and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.

Transmissible agents.

Flebogamma 10% 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.
The manufacturing process was investigated for its capacity to decrease infectivity of an experimental agent of transmissible spongiform encephalopathies (TSE) or the human equivalent of mad cow disease. These studies provided reasonable assurance that low levels of infectivity, if present in the starting material, would be removed.
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 10% 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.

Use in the elderly.

There is a limit experience in the elderly in clinical trials but no specific safety concerns have been identified in postmarketing experience to date.

Paediatric use.

It is recommended to monitor vital signs when administering Flebogamma 10% 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.

Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.
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 10% DIF should, therefore, only be given with caution to breastfeeding mothers.

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 10% DIF. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Adverse reactions such as chills, headache, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain have been observed.
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 have been observed with human normal immunoglobulin.
For safety with respect to transmissible agents, see Section 4.4 Special Warnings and Precautions for Use.

Tabulated summary of adverse reactions.

Flebogamma 10% DIF is likely to cause higher rate of adverse events than 5% product, possibly, but not certainly, due to increase rate of infusion likely to occur with the use of more concentrated product.
The adverse reactions categorised according to the MedDRA system organ class reported in any patient in the 3 trials are summarised separately by indications in Tables 2 and 3. Frequency of each adverse reaction calculated by infusions 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).
Summary of potentially related adverse events reported by patients with primary immunodeficiency.
Summary of potentially related adverse events reported by patients with chronic idiopathic thrombocytopenic purpura.

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.

Primary immunodeficiency disease.

One clinical trial IG 304 was performed with the objective of evaluating the clinical efficacy and the safety of the product. To achieve the primary objective it was used the Food and Drug Administration (FDA) efficacy criterion which includes as primary outcome the rate of serious bacterial infections of ≤ 1 serious bacterial infection/patient/year. The definition of serious bacterial infections includes the following infections: bacteraemia or sepsis, bacterial meningitis, osteomyelitis or septic arthritis, bacterial pneumonia or visceral abscess. These infections had to be diagnosed by essential diagnostic features listed but not all as symptoms, physical findings, laboratory tests and imaging studies. The study was designed as a multicenter, open label, nonrandomized, clinical study in patients with PID diseases requiring antibody replacement therapy and who have been receiving IVIG replacement therapy at a steady dose for at least 3 months prior to entry. Patients participated in the study for 12 months (13 to 17 infusions based on individual dose intervals). Study participants have received Flebogamma 10% DIF intravenously at a dose of 300 to 600 mg/kg per infusion, administered every 21 or 28 days (± 4 days). Forty six patients were enrolled in the study and received at least 1 infusion of Flebogamma 10% DIF. Thirty seven patients (80.4%) completed the study.
The results obtained from the trial with Flebogamma 10% DIF in PID (study IG304) show that patients who received Flebogamma 10% DIF infusions of 300-600 mg/kg had a serious bacterial infection rate of 0.025 infections/patient/year (1 serious bacterial infection reported; 98% CI = 0.001-0.133).

Chronic idiopathic thrombocytopenia.

Twenty seven patients, eighteen adults at least 18 years of age, and nine children aged 3-15 years were enrolled in 2 open trials in which patients with chronic ITP were treated with a total dose of 2 g/kg of Flebogamma 10% DIF. The primary efficacy response was the proportion of patients with increase in platelet count to ≥ 50 x 109/L.
Twenty four patients overall (89%) responded. The proportion of adult responders was 83% (15/18); the proportion of paediatric responders was 100% (9/9). The median time to response was ≤ 2 days for all the patients. The median duration of response was ≥ 13 days in all the patients. Responders recorded a median maximum platelet count of 237 x 109/L overall. Median time to maximum platelet count was 5 days.

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 Cmax, AUC, half-life, clearance and volume of distribution for total IgG and subclass IgG were determined in a subgroup of 19 patients (18-58 years; 10 male). Mean trough IgG level ranged from 880 to 976 mg/dL for 21 day infusion schedule patients and from 800 to 862 mg/dL for 28 day infusion schedule patients. The mean serum half-life for total IgG was 34 and 37 days for the 21 and 28 day dosing schedule, respectively, and the mean clearances were 115 and 144 mL/day. For IgG subclasses the mean serum half-life ranged from 28 to 51 days. For both dosing schedules, the mean AUC levels for the total IgG was around 34,000 day.mg/dL, the mean Cmax levels was around 2,000 mg/dL, and the mean volume of distribution between 5.4 and 7.5 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 10% DIF.

Carcinogenicity.

No carcinogenicity studies have been conducted with Flebogamma 10% DIF.

6 Pharmaceutical Particulars

6.1 List of Excipients

D-sorbitol.
Water for injections.
Flebogamma 10% 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 10% DIF is a solution for infusion supplied in a type II glass vial closed with a chloro-butyl-rubber stopper.
Flebogamma 10% DIF is supplied as 5 g/50 mL, 10 g/100 mL and 20 g/200 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.

6.7 Physicochemical Properties

Chemical stucture.

No data available.

CAS number.

None assigned.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes