Consumer medicine information

Intragam 10

Immunoglobulin, normal (human)

BRAND INFORMATION

Brand name

Intragam 10

Active ingredient

Immunoglobulin, normal (human)

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Intragam 10.

What is in this leaflet

This leaflet answers some common questions about Intragam® 10. It does not take the place of talking to your doctor. It does not contain all the available information about Intragam® 10.

All medicines have risks and benefits. Your doctor has weighed the benefits of you receiving Intragam® 10 against the possible risks.

If you have any concerns about receiving this medicine, ask your doctor. Follow your doctor’s advice even if it is different from what this leaflet says.

Please read this leaflet carefully and keep it as you may need to read it again.

The information in this leaflet is subject to change. Please check with your doctor whether there is any new information about this medicine that you should know since you were last treated.

What Intragam® 10 is used for

Your medicine is Intragam® 10, a solution for intravenous infusion. Intragam® 10 contains human immunoglobulins and is manufactured from human plasma (the liquid component of blood) collected by Australian Red Cross Lifeblood. Immunoglobulins are also called antibodies and are a type of protein found in the blood. Immunoglobulins are produced by your body’s immune system to fight infections caused by bacteria and viruses. If you do not have enough antibodies you may not be able to fight off diseases.

Your doctor may give you Intragam® 10 either for:

  • the replacement of antibodies because your antibody levels are low (referred to as immunodeficiency), or
  • a condition where there is an imbalance in your immune system requiring treatment with antibodies (referred to as immunomodulation).

Your doctor may have prescribed Intragam® 10 for another reason. Ask your doctor if you have any questions about why Intragam® 10 has been prescribed for you.

Before you are given Intragam® 10

Make sure you tell your doctor of any reasons you know of why you should not be given this medicine.

Inform your doctor of your blood group, if known.

You must not be given this medicine if you have:

  • a history of allergy to human immunoglobulin products (allergic reactions may include skin rash, face swelling, wheezing or breathing difficulties) or previously been told you react to any of the ingredients in Intragam® 10 (human immunoglobulins or glycine)
  • been told you have antibodies to immunoglobulin A (IgA)

Tell your doctor if you have, or have had, any of the following medical conditions:

  • allergy to human immunoglobulin products or to glycine. Some of the symptoms of an allergic reaction may include rash, itchiness, swelling of the lips and tongue, shortness of breath.
  • allergies to any other medicines, or if you have ever had an allergic reaction to an injection
  • a history of heart, or blood vessel disease, or blood clots, have thick blood, have been immobile for some time. Also tell the doctor what medicine you are using as some medicines, such as those that contain the hormone estrogen (for example, birth control pills), may increase your risk of developing a blood clot.
  • high blood pressure
  • low blood volume (hypovolaemia)
  • a condition that causes low antibody levels in your blood (IgA deficiency, hypogammaglobulinaemia or agammaglobulinaemia with or without IgA deficiency)
  • diabetes
  • kidney problems or kidney disease
  • a history of frequent headaches or migraine
  • any other medical conditions.

It is also important that you tell your doctor if you:

  • have blood group A, B or AB
  • are pregnant, intending to become pregnant or are breast-feeding
  • have had any vaccination within the last two weeks
  • are dehydrated
  • are taking any other medicines, including herbal or complementary medicines.

How Intragam® 10 is given

Your doctor will determine the dose(s) of Intragam® 10 that you will receive. Intragam® 10 is administered as an intravenous infusion (an injection given slowly into a vein).

On the day of your infusion make sure you have had sufficient fluids which will help reduce the risk of side effects.

While you are having Intragam® 10

This medicine is not expected to affect your ability to drive a car or operate machinery.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you obtain without a prescription from your pharmacy, supermarket or health food shop.

Vaccinations: Please inform your doctor if you are planning to have a vaccination. Intragam® 10 may impair the effect of some virus vaccines such as measles, mumps, rubella and chicken pox for a period of at least 6 weeks, and up to 3 months. After receiving this medicine, a period of 3 months should be allowed before vaccination with some virus vaccines. In the case of measles vaccine, this effect may last for up to 1 year, so if you are going to receive a measles vaccine you should have your measles antibody status checked.

Things you must do:

  • If you experience any of the effects listed in the side effects section of this leaflet or any other abnormal signs after treatment, tell your doctor immediately.
  • If you are about to be started on any new medicine, remind your doctor that you have been given Intragam® 10. Tell any other doctors, dentists, and pharmacists who treat you that you have been given this medicine.
  • If you are about to have any blood tests, tell your doctor that you have been given this medicine. It may interfere with the results of some tests.

Things to be careful of:

  • If having an infusion makes you feel light headed, dizzy or faint, be careful when getting up from a sitting or lying position. Getting up slowly may help.
  • Some patients may develop delayed reactions to Intragam® 10. These reactions occur after the infusion has stopped but usually within 24 hours.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are being given Intragam® 10, even if you do not think how you feel is connected with your medicine.

Along with their intended effects, medicines occasionally cause unwanted effects (side effects) in some people, some of which are serious. Side effects are more common with the first dose of Intragam® 10. Different people may react differently to similar doses of the same product. This applies to Intragam® 10. Most side effects tend to be related to the rate of infusion and are likely to occur during the first hour of infusion. If a side effect occurs, the nurse or doctor may reduce the rate of infusion or the infusion may be stopped.

If you are over 65 years you may have an increased chance of experiencing a side effect.

Do not be alarmed by the following lists of possible side effects. You may not experience any of them. If you have any questions, ask your doctor.

Tell your doctor if you notice any of the following:

This list includes the more common side effects of Intragam® 10. They are usually mild and short-lived.

  • headache
  • nausea
  • lethargy
  • pain in a joint
  • vomiting
  • pain in a muscle
  • infusion site reaction/pain
  • fever
  • dizziness
  • pain
  • hot flush
  • migraine
  • musculoskeletal stiffness
  • itchiness
  • pain in the abdomen
  • rash
  • skin peeling and redness
  • diarrhoea
  • paleness of skin
  • increased heart rate.

If you experience any of the following, tell your doctor immediately or go to the Emergency Department at your nearest hospital:

  • decreased alertness or difficulty in speaking
  • tingling, numbness or weakness on one or both sides of the body
  • pain/tenderness, swelling/discolouration of an arm or leg
  • shortness of breath
  • chest pain
  • skin becoming yellow
  • dark urine
  • decreased urine.

In rare cases this type of medicine may cause a sudden fall in blood pressure or a condition called anaphylactic shock, which is an allergic reaction that has symptoms such as low blood pressure (feeling faint) and difficulty breathing.

Severe headache, neck stiffness, drowsiness, fever, inability to stand bright light or painful eye movements may occasionally occur after receiving this medicine.

This list includes very serious side effects. You may need urgent medical attention or hospitalisation if you experience any of these side effects.

Other side effects not listed above, including inflammation of blood vessels and change in liver function, may also occur in some people. Some of these side effects may not cause symptoms and may only be found when your doctor does tests from time to time to check your progress.

Important information about some of the ingredients in Intragam® 10

When medicines are made from human blood or plasma, processes are used to prevent infections being passed from the blood/plasma donor to the person receiving the medicine. These processes include careful selection of the people who donate blood and plasma to make sure that those who might be carrying infections are excluded. In addition, each donation and pools of donations are tested for indicators of virus/virus infection(s).

Manufacturers of these medicines also include steps in the processing of blood or plasma that inactivate or remove viruses. Despite these processes, when medicines are prepared from human blood or plasma, the possibility of passing on an infection cannot be totally ruled out. Unknown or new viruses or other types of infection could also be passed on.

However, the measures taken in the manufacture of this medicine are considered effective for enveloped viruses such as human immunodeficiency virus, hepatitis B virus, and hepatitis C virus, and for the non-enveloped viruses hepatitis A and B19 virus (B19V).

There is reassuring clinical experience regarding the lack of hepatitis A or B19V infections with immunoglobulins. The antibodies which are in Intragam® 10 may make an important contribution to limiting the possibility an infection could also be passed on.

Please discuss the risks and benefits of this product with your doctor.

If you receive too much (overdose)

As Intragam® 10 is given to you under the supervision of your doctor or trained medical professional, it is very unlikely that you will receive an overdose. If you experience any side effects, tell your doctor immediately.

Further information

Intragam® 10 can only be obtained on a doctor’s prescription. This leaflet does not contain all the available information about Intragam® 10. If you require further information about Intragam® 10 and your treatment generally, or if you have any questions or are not sure about something in this leaflet, consult your doctor.

Storing Intragam® 10

You will normally be given this medicine in hospital. You will probably not need to keep any bottles of Intragam® 10. However, if you have to keep this medicine at home it should be stored refrigerated (2°C to 8°C) but not frozen. Once removed from refrigeration, store below 25°C and use within 3 months. Protect this medicine from light by keeping the bottles in their cartons.

Disposal

If your doctor stops your treatment or this medicine has passed its expiry date, ask your hospital or pharmacist what to do with any that is left over.

Product description

What it looks like

Intragam® 10 is a clear, colourless or pale yellow liquid. It is supplied in glass bottles.

Ingredients

Intragam® 10 is a sterile solution containing 10% plasma proteins of which at least 98% are immunoglobulins. Intragam® 10 does not contain any preservatives. Intragam® 10 is packaged in latex free materials.

Manufacturer

Intragam® 10 is manufactured in Australia by:

CSL Behring (Australia) Pty Ltd
ABN 48 160 734 761
189–209 Camp Road
Broadmeadows VIC 3047
Australia

Distributor

Australian Red Cross Lifeblood

Date of revision

April 2020

Australian Register Numbers

25 mL: AUST R 162486

50 mL: AUST R 162487

100 mL: AUST R 162488

200 mL: AUST R 162489

® Registered trademark of CSL Limited

Published by MIMS June 2020

BRAND INFORMATION

Brand name

Intragam 10

Active ingredient

Immunoglobulin, normal (human)

Schedule

S4

 

1 Name of Medicine

Human normal immunoglobulin.

2 Qualitative and Quantitative Composition

Intragam 10 is a sterile, preservative free, clear or slightly opalescent and colourless or pale yellow solution for intravenous infusion. Intragam 10 contains 10% (10 g/100 mL) of human plasma protein with a purity of at least 98% immunoglobulin G (IgG). At least 90% of the IgG consists of monomers and dimers (typically > 96%). Aggregates are < 3%. The distribution of the IgG subclasses closely resembles that found in normal human plasma (approximate mean ranges: 47.6-56.2% IgG1, 41.5-49.5% IgG2, 1.3-1.6% IgG3, 0.9-1.3% IgG4).
Intragam 10 has a nominal osmolality of 350 mOsmol/kg and is approximately isotonic. The pH value of the ready-to-use solution is 4.25 (4.05-4.45). Intragam 10 contains 2.25 g of glycine in each 100 mL as a stabiliser which is a physiological non-essential amino acid. Intragam 10 does not contain a carbohydrate stabiliser (e.g. sucrose, maltose) and contains no preservative. Intragam 10 contains only trace amounts of IgA, typically < 0.025 mg/mL. The maximum prekallikrein activator (PKA) levels are less than 28.6 IU/mL (typically ≤ 1.2 IU/mL).
Intragam 10 is manufactured from human plasma collected by Australian Red Cross Lifeblood.

4 Clinical Particulars

4.1 Therapeutic Indications

Intragam 10 is indicated for replacement IgG therapy in:
Primary Immunodeficiency Diseases (PID).
Symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.
Intragam 10 is indicated for immunomodulatory therapy in:
Idiopathic Thrombocytopenic Purpura (ITP), in adults or children at high risk of bleeding or prior to surgery to correct the platelet count.
Kawasaki disease.
Guillain-Barré Syndrome (GBS).
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP).
Multifocal Motor Neuropathy (MMN).
Myasthenia Gravis (MG) in acute exacerbation (myasthenic crisis) or prior to surgery and/or thymectomy; as maintenance therapy for moderate to severe MG when other treatments have been ineffective or caused intolerable side effects.
Short-term therapy for severely affected nonparaneoplastic Lambert-Eaton Myasthenic Syndrome (LEMS) patients.
Treatment of significant functional impairment in patients who have a verified diagnosis of stiff person syndrome.

4.2 Dose and Method of Administration

Dosage.

The dosage recommendations are summarised in Table 1.

Administration.

Caution.

This product does not contain an antimicrobial preservative. It must, therefore, be used immediately after opening the bottle. Any unused solution should be discarded appropriately. Use in one patient on one occasion only. Do not use if the solution has been frozen.
The solution must be clear or slightly opalescent. If it appears to be turbid or to contain any sediment, it must not be used and the bottle should be returned unopened to Australian Red Cross Lifeblood.
Allow the preparation to reach room temperature before use. Intragam 10 should be administered through a standard intravenous infusion giving set. The infusion line may be primed or flushed with 0.9% saline (0.9% sodium chloride solution). Intragam 10 should be administered separately from intravenous fluids (other than normal saline) or medications the patient might be receiving. Intragam 10 may be infused undiluted or diluted with up to 2 parts of 0.9% saline.
The infusion should be commenced at the rate of 1 mL per minute. After 15 minutes the rate may be gradually increased to a maximum of 3 to 4 mL per minute over a further 15 minutes. Infusion rates higher than recommended may increase the incidence of headache. Consideration should be given to reducing the rate of infusion in patients naive to Intragam 10, patients switching from an alternative IVIg, patients who have not received IVIg for a long time, paediatric and elderly patients and in patients with pre-existing renal disease (see Section 4.4 Special Warnings and Precautions for Use, General).

4.3 Contraindications

Intragam 10 is contraindicated in patients who have had a true anaphylactic reaction to human immunoglobulins (especially in patients with antibodies against IgA) or to the excipient glycine.

4.4 Special Warnings and Precautions for Use

General.

The recommended infusion rate of Intragam 10 must be closely followed (see Section 4.2 Dose and Method of Administration). Certain reactions (including severe reactions) to IVIg tend to be related to the infusion rate and are most likely to occur during the first hour of the infusion. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. In case of adverse reaction, the rate of administration should be reduced or the infusion stopped to alleviate symptoms. Once a reaction has resolved, based on clinical judgement, the infusion may cautiously be recommenced at a slower rate.
Certain adverse reactions may occur more frequently:
with a higher infusion rate;
in patients with hypo- or agammaglobulinemia 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 infusing the product slowly (1 mL/min);
patients are carefully monitored for any symptoms throughout the infusion period;
the infusion rate is reduced in patients who are naive to Intragam 10 or who are at increased risk of adverse events.

Hypersensitivity.

True hypersensitivity reactions to immunoglobulins are rare. They can occur in patients with anti-IgA antibodies, such as those with IgA deficiency. Intragam 10 should be used with caution in patients with a known allergy to constituents of the preparation. Intragam 10 contains traces of IgA which seldomly may provoke anaphylaxis in IgA deficient patients 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. In case of anaphylactic reaction, the infusion should be stopped immediately.

Acute renal failure.

Cases of renal dysfunction and acute renal failure have been reported in patients receiving IVIg therapy. Risk factors may include: pre-existing renal insufficiency, diabetes mellitus, hypovolaemia, concomitant nephrotoxic medicinal products, sepsis, paraproteinaemia, being overweight or aged over 65 years. The majority of cases of renal dysfunction and acute renal failure have been associated with the use of those IVIg products containing sucrose as a stabiliser. There is no sucrose in Intragam 10. In case of renal impairment, IVIg discontinuation should be considered. The following precautions should be followed for all patients at risk:
ensuring adequate hydration prior to the initiation of Intragam 10;
monitoring of urine output;
monitoring of serum creatinine levels;
avoidance of concomitant loop diuretics.
In patients at risk for renal failure, IVIg products should be administered at the minimum rate of infusion and dose practicable.

Thrombotic events.

There is clinical evidence of an association between IVIg administration and thromboembolic events 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 when prescribing and infusing IVIg for patients with pre-existing risk factors for thrombotic events such as advanced age, estrogen use, in-dwelling vascular catheters, a history of venous or arterial thrombosis, acquired or inherited hypercoagulable states, cardiovascular risk factors (including history of atherosclerosis and/or impaired cardiac output), prolonged periods of immobilisation, severe hypovolaemia, hyperviscosity (including cryoglobulins, fasting chylomicronaemia and/or high triglyceride levels, and monoclonal gammopathies). Reports have included cases of thrombophlebitis. In case of thromboembolic adverse reaction, the benefit and risk of treatment should be assessed before IVIg therapy is continued.
In patients at risk for thromboembolic adverse reactions, IVIg products should be administered at the minimum rate of infusion and dose practicable, and these individuals should be monitored for thrombotic complications. Ensure adequate hydration prior to the initiation of Intragam 10. Consideration should also be given to measurement of baseline blood viscosity in individuals at risk for hyperviscosity.

Aseptic meningitis syndrome.

Aseptic Meningitis Syndrome (AMS) has been reported in association with IVIg treatment. It has been hypothesised that IVIg-associated AMS is the severe presentation of a continuum that begins with the more common adverse event of headache. The AMS syndrome usually begins within several hours to two days following IVIg treatment. It is characterised by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis, predominantly from the granulocytic series, and elevated protein levels. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high dose (2 g/kg) IVIg treatment. Discontinuation of IVIg treatment has resulted in remission of AMS within several days without sequelae.
Patients with a history of AMS, migraine or frequent headaches may be more susceptible to the syndrome. For these patients the following precautions should be taken:
assessment of hydration status and ensuring adequate hydration prior to commencement of infusion of Intragam 10;
administration of a pre-medication (e.g. paracetamol/paracetamol and codeine) if needed prior to each infusion of Intragam 10 (e.g. if headache present);
administration of the minimum dose at the minimum rate 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 (Coombs' test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy due to enhanced red blood cells (RBC) sequestration. Patients at increased risk for haemolysis following treatment with immunoglobulin include those with blood groups A, B, or AB, or who have underlying associated inflammatory conditions. Also at risk are patients receiving high cumulative doses of immunoglobulin over the course of several days. IVIg recipients should be monitored for clinical signs and symptoms of haemolysis, particularly those patients at increased risk. If these occur, appropriate laboratory testing should be undertaken.

Acid load.

In patients with limited or compromised acid-base compensatory mechanisms including neonates, consideration should be given to the effect of the additional acid load that the preparation might present.

Pathogen safety.

This product is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses and theoretically Creutzfeldt-Jakob Disease (CJD) agents. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain infectious agents and by testing for the presence of certain pathogen markers. In addition, three dedicated pathogen reduction steps are included in the manufacturing process of Intragam 10 to reduce the possibility of pathogen transmission including pasteurisation (heating at 60°C for 10 hours), nanofiltration and incubation at low pH. The current procedures applied in the manufacture of this product are effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) viruses, and the non-enveloped viruses hepatitis A (HAV) and parvovirus B19. In addition, Intragam 10 contains specific antibodies directed against parvovirus B19.
Despite these measures, there remains the potential that such products may transmit disease. There is also the possibility that other known or unknown infectious agents may be present in such products. Vaccination of patients in receipt of plasma-derived therapeutics should be considered where appropriate.
It is recommended that the name and batch number of the product are recorded every time the product is administered to a patient.

Use in the elderly.

Clinical studies of Intragam 10 included a total of 22 subjects aged > 65 years. Based on these limited data, no overall differences in the safety profile were observed between subjects > 65 years and subjects 18 to 65 years of age.

Paediatric use.

The use of Intragam 10 in the paediatric population has not been established in clinical studies.

Effects on laboratory tests.

After immunoglobulin infusion 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 allo-antibodies (e.g. Coombs' test), reticulocyte count and haptoglobin.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Live attenuated virus vaccines.

Immunoglobulin infusion may impair the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella for a period of at least six weeks and up to three months. After infusion of Intragam 10, an interval of three months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to one year. Therefore patients receiving measles vaccine should have their antibody status checked. Additionally, immunoglobulins should not be administered for at least two weeks after these vaccines are given.
The interaction of Intragam 10 with other medicines has not been established.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No fertility studies have been conducted with Intragam 10.
No animal reproduction studies have been conducted with Intragam 10. Intragam 10 should be given to pregnant women only if clearly indicated.
An embryofoetal development study in which rats were infused IV with the excipient glycine 945 mg/kg/day on gestation days 6-17 showed no adverse effects.
No lactation studies have been conducted with Intragam 10. Immunoglobulins are excreted in breast milk and may contribute to the transfer of protective antibodies to the neonate.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Two clinical studies with Intragam 10 were performed, one study of 19 patients with PID and one study of 19 patients with ITP.
Causally related adverse reactions reported in these studies are summarised and categorised according to the MedDRA system organ class and frequency, calculated in percentage of patients in Table 2 (very common (≥ 10% patients), or common (≥ 1% and < 10% patients)).
Adverse events (AEs) reported by two or more patients (> 10%) in the studies, irrespective of causal relationship to the product, are presented in Table 3.
In a prospective observational post-authorisation safety study (PASS) to evaluate the occurrence of AMS in adults receiving ≥ 1 g/kg bw of Intragam 10 for a range of indications, the primary endpoint included the occurrence of AMS, migraine and severe headache. All 39 patients enrolled were either naive to IVIg or were switched to Intragam 10 from another IVIg product (see Section 5.1 Pharmacodynamic Properties). No occurrences (rate = 0%, 95% CI: 0.0 to 9.0%) of AMS or migraine were observed in this study. Severe headache occurred in 3 (7.7%) patients (2 considered serious). The following adverse events were reported in > 5% of patients: headache 10 (25.6%), musculoskeletal pain (including pain in extremities) 3 (7.6%), and rash 2 (5.2%). One patient with ITP experienced cerebrovascular accident, considered serious (outcome resolved).

General class effects associated with intravenous immunoglobulins.

True hypersensitivity reactions to IVIg products, such as urticaria, angioedema, bronchospasm, or a sudden drop in blood pressure, have been observed in patients. In isolated cases immunoglobulins may cause anaphylactic shock, even when the patient has shown no known hypersensitivity to previous administration (see Section 4.4 Special Warnings and Precautions for Use, Hypersensitivity). Should an anaphylactic reaction to Intragam 10 develop, the infusion should be stopped immediately and appropriate treatment initiated.
Adverse reactions (such as chills, headache, fever, vomiting, nausea, arthralgia, changes in blood pressure or moderate lower back pain) or allergic-type reactions (such as flushing, pruritus, lethargy, restlessness, tachycardia, tingling, tissue swelling, wheezing or shortness of breath) may occur occasionally with the use of IVIg products.
Other class adverse reactions that may occur with IVIg preparations include: malaise, abdominal pain, chest-tightness, facial flushing or pallor, erythema, hot sensations, respiratory difficulty, non-urticarial skin rash, cutaneous vasculitis, or infusion/injection site reactions (such as pain, swelling, erythema, pruritus or rash at the site).
Some patients may develop delayed adverse reactions to IVIg products such as: nausea, vomiting, chest pain, rigors, dizziness, aching legs or arthralgia. These adverse reactions occur after the infusion has stopped but usually within 24 hours.
Cases of reversible AMS (see Section 4.4 Special Warnings and Precautions for Use, Aseptic meningitis syndrome), isolated cases of reversible haemolytic anaemia/haemolysis (see Section 4.4 Special Warnings and Precautions for Use, Haemolytic anaemia), and cases of transient cutaneous reactions, have been reported with IVIg treatment. Neutropenia has been reported in rare instances. Increase in serum creatinine level and/or acute renal failure (see Section 4.4 Special Warnings and Precautions for Use, Acute renal failure) have been observed.
Mild and moderate elevations of serum transaminases (aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT)) have been observed in a small number of patients given IVIg. Such changes were transient and not associated with the transmission of hepatitis.
Very rarely, thrombotic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thromboses have been associated with IVIg treatment (see Section 4.4 Special Warnings and Precautions for Use, Thrombotic events).

Postmarketing experience.

In addition to the reactions observed in clinical trials, the following was observed postmarketing.

Skin and subcutaneous tissue disorders.

Exfoliative dermatitis.

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 with immunoglobulin products may lead to fluid overload and hyperviscosity, particularly in the elderly and in patients with cardiac or 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

Mechanism of action.

Intragam 10 contains functionally intact IgG with a broad spectrum of antibodies against infectious agents.
Intragam 10 contains the IgG antibodies present in the donor population. Adequate doses of human normal immunoglobulin restore abnormally low IgG levels to the normal range. The mechanism of action in indications other than replacement therapy is not fully elucidated, but includes immunomodulatory effects.
Intragam 10 is manufactured by chromatographic fractionation. It is prepared from pooled plasma collected from not fewer than 1000 donors. The IgG molecules have not been chemically or enzymatically modified and the Fc and Fab functions are retained. It has an IgG subclass distribution closely proportional to normal human plasma. The manufacturing process contains three dedicated and complementary steps to reduce the possibility of pathogen transmission:
pasteurisation (60°C for 10 hours);
nanofiltration;
incubation at low pH.

Clinical trials.

Replacement therapy.

Intragam P is CSL's 6% w/v intravenous immunoglobulin (IVIg) and parent product for Intragam 10 which differs from Intragam P only in formulation, concentration and additional pathogen removal step as part of the manufacturing process. The efficacy of Intragam 10 in PID is confirmed by previous clinical trials conducted with Intragam P, as the biological, pharmacokinetic and safety data showed no significant differences between the two products. Therefore, the following clinical trial information for Intragam P supports the efficacy of Intragam 10 in PID patients.
The efficacy of Intragam P was assessed in 35 subjects (age 6-76 years; 21 male) with PID, following the administration of monthly intravenous infusions of Intragam P for six months. The dose of Intragam P was individualised in the range 0.2 to 0.67 g/kg bw. The mean number of days of hospitalisation over the 6 month period was 2.8 ± 9.0 and the mean number of days absent from work or school due to illness was 5.3 ± 6.4. These figures were similar to historical data relating to other IVIgs.

Immunomodulatory therapy.

The efficacy of Intragam 10 in patients with ITP was established in a multicentre open label clinical trial, which was consistent with the results from the previous Intragam P clinical trials. A total of 17 subjects aged 20 to 76 years with ITP and a platelet count of < 50 x 109/L were treated with 1 g/kg bw of Intragam 10 on each of two consecutive days (a total cumulative dose of 2 g/kg bw). A rise in platelet count to at least 50 x 109/L within 7 days after the first infusion was observed in 15 of the 17 subjects studied. The median time to achieve this platelet response was 4 days after the first infusion, and 71% of the subjects reached this response within four days (i.e. two days after the second infusion). For those subjects who responded, the median duration of platelet count ≥ 50 x 109/L was 17 days (range: 7 to > 85 days).
A prospective observational PASS was conducted to evaluate the occurrence of AMS in adults receiving ≥ 1 g/kg bw of Intragam 10 for a range of indications. The primary endpoint included the occurrence of AMS, migraine and severe headache. A total of 39 patients were enrolled in the study, aged 23 to 84 years, who had neurologic and haematologic conditions requiring immunoglobulin therapy for immunomodulation or immune replacement. The mean dose was 1.74 g/kg bw and the median total dose was 2.0 g/kg bw. A total of 143 infusions were given, with a median maximum infusion rate of 240 mL/hr (range: 60 to 700 mL/hr). The majority of the patients were naive to IVIg treatment (30 of 39 patients; 76.9%). Throughout the treatment period and up to 7 days after the last Intragam 10 infusion, the most common adverse event observed was headache which occurred in 10 patients (25.6%). Severe headache was reported in 3 patients (7.7%; 95% CI: 1.62 to 20.87%). Neither AMS nor migraine (0%, 95% CI: 0.0 to 9.0%) were observed. One patient was withdrawn due to moderate rash occurring during the first infusion.
There are several other randomised controlled clinical trials available in literature demonstrating the safety and efficacy of IVIg treatment in patients with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Multifocal Motor Neuropathy (MMN) and Myasthenia Gravis (MG). Whilst the evidence for safety and efficacy of IVIg in the management of CIDP and acute exacerbations of MG is clear, data for the treatment of chronic MG and MMN is not yet as definitive. Clinical trials for the use of IVIg for MMN showed an increase in muscle strength but no impact on the disability scale.
The safety and efficacy of IVIg in the treatment of patients with stiff person syndrome and Lambert-Eaton Myasthenic Syndrome (LEMS) has only been demonstrated in a single randomised controlled clinical trial for each condition.
The adverse reactions reported in the literature for IVIg when used in CIDP, MMN, MG, LEMS and stiff person syndrome were consistent with those reported for other IVIg indications (see Section 4.8 Adverse Effects (Undesirable Effects)).
Intragam 10 has shown overall similar characteristics to other IVIg products used in the management of CIDP, MMN, MG, LEMS and stiff person syndrome.

5.2 Pharmacokinetic Properties

Intragam 10 is immediately and completely bioavailable in the recipient’s circulation after intravenous infusion. It is distributed relatively rapidly between plasma and extravascular fluid. After approximately 3 to 5 days, equilibrium is reached between the intra- and extravascular compartments.
The pharmacokinetic parameters for Intragam 10 were established in a clinical study (see Section 5.1 Pharmacodynamic Properties, Clinical trials) in patients with Primary Immunodeficiency Disease (PID). Nineteen patients (aged 18 to 69 years) participated in the pharmacokinetic assessment (see Table 4). The median half-life of Intragam 10 in patients with PID was 34 days. This half-life may vary from patient to patient. 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 Intragam 10.

Carcinogenicity.

No carcinogenicity studies have been conducted with Intragam 10.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

See Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C. (Refrigerate. Do not freeze.)
Once removed from refrigeration, store below 25°C and use within 3 months. Do not return to refrigeration.
Protect from light.
Do not use after the expiry date.

6.5 Nature and Contents of Container

The following presentations in Table 5 are registered for Intragam 10.
Intragam 10 is packaged in latex free materials.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

No data available.

CAS number.

9007-83-4.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes