Transfusion medicine handbook

5. Fractionated Products

5.4.10 INTRAGAM P (Human Normal Immunoglobulin 6%)

Privigen NZ will replace Intragam P as the intravenous immunoglobulin (IV Ig) product manufactured from New Zealand plasma in the second half of 2023. Inventory of Intragam P will continue to be used until early 2024, where at which point it will be discontinued.

Intragam P is a sterile, preservative free solution containing 6 g of human protein and 10 g of maltose in each 100 mL, available in 10 mL (0.6 g), 50 mL (3 g) and 200 mL (12 g) vials [17]. Intragam P is made by chromatographic fractionation of large pools of human plasma obtained from New Zealand's voluntary and non-remunerated blood donors. Intragam P is intended for intravenous administration.

Intragam P contains only trace amounts of IgA (typically <0.025 mg/mL). The manufacturing process contains specific steps to reduce the possibility of virus transmission including pasteurisation (heating at 60°C for 10 hours) and incubation at low pH [17].

Indications for Use

See Table 5.19 for the indications listed on the New Zealand data sheet.

Table 5.19: Indications for Use of Intragam P [17]

In addition, intravenous immunoglobulin has an established and emerging therapeutic role in a wide range of autoimmune and inflammatory diseases including chronic inflammatory demyelinating polyneuropathy, inflammatory myopathies, Lambert–Eaton myasthenic syndrome, multifocal motor neuropathy, myasthenia gravis, and stiff-person syndrome. Intragam P is not registered for these indications in New Zealand and issue of this product is subject to consultation between the specialist physician and a NZBS Transfusion Medicine Specialist/ Medical Officer.

Comprehensive evidence-based guidelines for the use of intravenous immunoglobulin are lacking. Substitutes, such as the Criteria for the Clinical Use of Intravenous Immunoglobulin in Australia (the Criteria) https://www.criteria.blood.gov.au/ and the Clinical Guidelines for Immunoglobulin Use https://www.gov.uk/government/publications/clinical-guidelines-for-immunoglobulin-use-second-edition-update provide guidance about recognised uses.

Intragam P is also used to provide passive antibodies for treatment or post-exposure prophylaxis of certain infections in some circumstances:

• No specific immunoglobulin product available (e.g. Zoster Immunoglobulin-VF)
• Immunosuppressed or immune-deficient contacts (who may, for example, have a central venous catheter)
• Individuals with reduced muscle bulk
• Intramuscular injection is contraindicated
• Large doses are required.

The NZBS document 111G01001 INTRAGAM P DOSES FOR ZOSTER, TETANUS, CMV ANTIBODY contains guidance in relation to dosing and rounding according to vial size. Specific antibody levels useful for calculation of dosing:

• Herpes zoster 10 IU/mL
• Tetanus 10.40 IU/mL
• CMV 4093.70 U/mL

Dosing for measles post-exposure prophylaxis is 0.15 g/kg which may provide approximately 11 IU/kg [18].

Dosage and Administration

Intragam P may be infused undiluted. It may also be infused diluted with up to 2 parts of 0.9% saline or 5% glucose.

• 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 - 4 mL per minute over a further 15 minutes.
• Too rapid a rate of infusion may cause flushing and changes in heart rate and blood pressure.
• Patients naive to Intragam P, switching from an alternative IVIg product, or who have not received IVIg for a long time, should be closely monitored during the first infusion.
• In patients at risk for acute renal failure or thrombotic events, IVIg products should be administered at the minimum rate of infusion and dose practicable.

Replacement Therapy

• The optimal dose and frequency of administration of Intragam P must be determined for each patient. Freedom from recurrent bacterial infections is usually achieved with a serum IgG level > 5 g/L.
• Most patients initially receive 400 mg IgG per kilogram body weight, followed by monthly maintenance doses of at least 200 mg per kilogram body weight.
• The monthly maintenance dose, guided by the patient's clinical status and pre-infusion (trough) serum IgG level, is often 300 - 450 mg of IgG per kilogram body weight.
• As catabolic rates vary, the IgG levels of new patients should be monitored regularly for several monthly cycles to determine the effective dose.

Immunomodulatory Therapy

Primary Immune Thrombocytopenia

• Patients should receive up to a maximum total cumulative dose of 2.0 g IgG per kilogram body weight, over 2 - 5 days.

Kawasaki Disease

• Patients should receive 1.6 - 2.0 g IgG per kilogram body weight, administered in divided doses over 2 - 5 days, or 2.0 g IgG per kilogram body weight as a single dose.

Guillain-Barré Syndrome

• Patients should receive 0.4 g IgG per kilogram body weight per day for five days.

Further guidance on dosing is available in the Criteria for the Clinical Use of Intravenous Immunoglobulin in Australia (the Criteria) https://www.criteria.blood.gov.au/

Contraindications

Intragam P is contraindicated in individuals who have had a true anaphylactic reaction to the active substance or the excipient.

Precautions

• Administration
  Intragam P should only be administered intravenously. It is possible that Intragam P may on rare occasions, cause a precipitous fall in blood pressure and a clinical picture of anaphylaxis. Therefore, adrenaline and oxygen should be available for the treatment of such an acute reaction.
• Aseptic meningitis
  Aseptic meningitis syndrome has been reported to occur infrequently in association with IVIg treatment.
• IgA antibodies
  Intragam P contains trace amounts of IgA which may provoke anaphylaxis in patients with IgA antibodies, such as those with IgA deficiency.
• Positive direct antiglobulin tests and red cell haemolysis
  Positive direct antiglobulin tests and red cell haemolysis have been reported following high dose infusion of intravenous immunoglobulin due to the presence of anti-A, anti-B, and occasionally with anti-D or other erythrocyte antibodies in the product. Such red cell sensitisation may cause crossmatching difficulties and transient haemolytic anaemia.
• Renal dysfunction
  There have been reports of renal dysfunction and acute renal failure in patients receiving IVIg. Patients should be adequately hydrated prior to administration of IVIg.
• Thromboembolism
  Thrombotic events have been reported in association with IVIg therapy. Caution should be exercised in prescribing and administering Intragam P in patients with pre-existing risk factors for thrombotic events.
• Thrombophlebitis
  Prolonged administration (over 6 hours) using large doses (greater than 400 mg/kg) may result in thrombophlebitis at the infusion site.

Adverse Reactions

Reactions to intravenous immunoglobulin tend to be related to the infusion rate and are most likely to occur during the first hour of the infusion. It is recommended that the patient's vital signs and general status be monitored regularly throughout the infusion.

The types of reactions that may occur include: malaise, abdominal pain, headache, chest-tightness, facial flushing or pallor, hot sensations, dyspnoea, non-urticarial skin rash, itching, arthralgia, tissue swelling, hypotension, nausea, or vomiting. Should any of these reactions develop during infusion of Intragam P, the infusion should be temporarily stopped (5 - 10 minutes) until the patient improves clinically and then cautiously recommenced at a slower rate.

Allergic reactions are most likely to occur during the first hour of the infusion.

True hypersensitivity reactions to intravenous immunoglobulin such as urticaria, angioedema, bronchospasm or hypotension occur very rarely. Should an anaphylactic reaction to Intragam P develop, the infusion should be stopped, and immediate treatment instituted with adrenaline and oxygen.

Interactions with Other Medicines

Passively acquired antibody can interfere with the response to live attenuated virus vaccines such that vaccine administration should be deferred for at least 3 months. In the case of measles and varicella vaccines following IVIg products, the impairment may persist for up to 12 months. Where deferral is impractical, patients receiving such vaccines should have their antibody response checked. By the same token, immunoglobulins should not be administered for at least two weeks after live attenuated vaccines are given. Consultation with a NZBS Transfusion Medicine Specialist/ Medical Officer is recommended.

Interaction with Capillary Glucose Measurement

Caution should be exercised when interpreting blood sugar levels in patients receiving Intragam P. The maltose present in Intragam P may result in falsely elevated capillary blood glucose levels with some types of glucose meters. If this measurement is used to guide treatment, hypoglycaemia may occur.

When monitoring glucose levels in patients receiving Intragam P consult the product information and/or manufacturer of the glucose meter and test strips (including those used at home by patients) to ensure that maltose does not interfere with the blood glucose reading.