Human Normal Immunoglobulin (160mg per ml)

Registered South African indications:

Indications for subcutaneous administration (SCIg)

• Replacement therapy in adults, children and adolescents (0-18 years) in:
  - Primary immunodeficiency syndromes with impaired antibody production
  - Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia (CLL), in whom prophylactic antibiotics have failed or are contraindicated
  - Hypogammaglobulinaemia and recurrent bacterial infections in multiple myeloma (MM) patients
  - Hypogammaglobulinaemia in patients pre- and post-allogeneic haematopoietic stem cell transplantation (HSCT)

Indications for intramuscular administration (IMIg)

• Hepatitis A prophylaxis in adults and children and adolescents (0-18 years):
  - Pre-exposure prophylaxis, preferably in combination with vaccination, in unvaccinated individuals travelling in less than 2 weeks to areas of hepatitis A risk
  - Post-exposure prophylaxis in unvaccinated individuals within 2 weeks of hepatitis A virus (HAV) exposure

Consideration should also be given to other official guidance on the appropriate use in hepatitis A prophylaxis. For long term hepatitis A prophylaxis, vaccination is recommended

• Therapy of radiogenic mucositis

Contraindications

Registered contraindications in South Africa & other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Human normal immunoglobulin must not be given intravascularly
• Must also not be administered intramuscularly in cases of severe thrombocytopenia and in other disorders of haemostasis

Cautions

Recommendations in South Africa & other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly

The listed warnings and precautions apply both to adults and children

Intravascular injection

• Do not inject human normal immunoglobulin intravascularly
• Accidental intravascular administration may lead to shock
• The recommended infusion rate must be strictly followed
• Patients should be closely monitored and observed for adverse reactions throughout the infusion

Adverse reactions and monitoring

• Certain adverse reactions may be more frequent in first-time users of human normal immunoglobulin, or in those switched to normal immunoglobulin, or when dosing intervals are irregular
• Complications may often be avoided by initiating infusion at a slow rate (10ml/hr) and monitoring patients closely during the infusion period, especially:
  • Treatment-naïve patients
  • Patients switching from another immunoglobulin medicine
  • Patients with irregular treatment intervals
• These patients should be monitored during and for at least 1 hour after the first infusion
• All other patients should be observed for at least 20 minutes after administration

Anaphylactic reactions

• If an allergic or anaphylactic reaction is suspected, discontinue administration immediately
• Treatment should be based on the nature and severity of the reaction
• In case of shock, implement standard medical treatment protocols

Hypersensitivity

• True allergic reactions are rare but may occur, particularly in patients with anti-IgA antibodies
• Patients with anti-IgA antibodies should be treated with caution and only receive human normal immunoglobulin under close medical supervision if subcutaneous IgG therapy is the only option
• Rarely, human normal immunoglobulin may cause a drop in blood pressure with an anaphylactic reaction, even in patients who previously tolerated the treatment

Thromboembolism

• Arterial and venous thromboembolic events such as myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism have been reported with immunoglobulin use
• Patients should be adequately hydrated prior to immunoglobulin administration
• Caution is advised in patients with risk factors for thromboembolic events, including advanced age, hypertension, diabetes mellitus, history of vascular disease or thrombosis, acquired or inherited thrombophilic conditions, prolonged immobilisation, hypovolaemia, or conditions increasing blood viscosity
• Patients should be informed of the signs and symptoms of thromboembolism (e.g. unexplained cough, shortness of breath, limb pain or swelling, focal neurological symptoms, chest pain) and instructed to seek medical attention immediately if these occur

Aseptic meningitis syndrome (AMS)

• AMS has been reported with subcutaneous immunoglobulin treatment, typically occurring within several hours to 2 days after administration
• Symptoms usually resolve within a few days after discontinuing treatment, without sequelae
• Patients should be informed about early symptoms such as severe headache, neck stiffness, drowsiness, fever, photophobia, nausea, and vomiting

Interference with serological testing

• A temporary increase in passively transferred antibodies may lead to misleading positive results in serological tests following immunoglobulin administration
• Passive transfer of antibodies to erythrocyte antigens (e.g. A, B, D) may interfere with red cell antibody testing, including the direct antiglobulin test (DAT or direct Coombs' test)

Transmissible agents

• Human normal immunoglobulin is derived from human plasma, and standard safety measures are in place including donor selection, donation screening, and virus inactivation/removal steps during manufacturing
• Despite these precautions, the transmission of infectious agents cannot be completely ruled out
• This includes known, unknown, or emerging viruses and other pathogens
• The manufacturing process is considered effective against enveloped viruses (e.g. HIV, HBV, HCV) and non-enveloped viruses (e.g. HAV, parvovirus B19)
• Clinical experience supports a low risk of hepatitis A or parvovirus B19 transmission with immunoglobulins, likely due to protective antibody content

Traceability

• It is strongly recommended that the name and batch number of human normal immunoglobulin be recorded every time it is administered to ensure traceability between the product and the patient

Effects on ability to drive and use machines

• The ability to drive and operate machines may be impaired by some adverse reactions associated with human normal immunoglobulin. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines

Additional South African recommendations

Sodium content

• Human normal immunoglobulin contains up to 110mg (4.78 mmol) sodium per dose for a 75kg person receiving the maximum daily dose (11.25g = 70.3ml)
• This should be considered in patients on a controlled sodium diet

Recommendations in other jurisdictions

Sodium content

• Human normal immunoglobulin contains up to 4.6mg sodium per ml
• This is equivalent to 2.5% of the WHO recommended maximum daily intake of 2g sodium for an average 80kg adult

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Note: Formulations of human normal immunoglobulin vary in their approved routes of administration. Always check the product packaging and accompanying information to confirm suitability for intramuscular and/or subcutaneous use before administration

The dose and dose regimen are dependent on the indication

Indications for subcutaneous administration (SCIg)

Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency

Replacement therapy in:
Primary immunodeficiency syndromes with impaired antibody production
Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia (CLL), in whom prophylactic antibiotics have failed or are contraindicated
Hypogammaglobulinaemia and recurrent bacterial infections in multiple myeloma (MM) patients
Hypogammaglobulinaemia in patients pre- and post-allogeneic haematopoietic stem cell transplantation (HSCT)

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

• SC: Should achieve a trough level of IgG (measured before the next infusion) of at least 5 to 6g/l; Aim to be within the reference interval of serum IgG for age; Loading dose: At least 0.2 to 0.5g/kg (1.3 to 3.1ml/kg) body weight may be required; This may need to be divided over several days; Max: 0.1 to 0.15g/kg/24hrs

- Maintenance doses

• SC: After steady state IgG levels have been attained, maintenance doses are administered at repeated intervals (approx. once per week) to reach a cumulative monthly dose of the order of 0.4 to 0.8g/kg; Each single dose may need to be injected at different anatomic sites

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The medicine should be administered via the subcutaneous route

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Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dose and aim for higher trough levels

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Method of administration: See additional prescribing points

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Indications for intramuscular administration (IMIg)

Hepatitis A prophylaxis
- Pre-exposure prophylaxis, preferably in combination with vaccination, in unvaccinated individuals travelling in less than 2 weeks to areas of hepatitis A risk (short-term prophylaxis)

To achieve a minimum protective level of 10mIU/ml with an IMIg with a minimum antibody content for HAV of 100 IU/ml, the following dose is recommended:

• IM: For stays in endemic areas of less than 3 months: 0.17ml/kg body weight (preferably given in combination with vaccination)

- Post-exposure prophylaxis in unvaccinated individuals within 2 weeks of hepatitis A virus (HAV) exposure

To achieve a minimum protective level of 10mIU/ml with an IMIg with a minimum antibody content for HAV of 100 IU/ml, the following dose is recommended:

• IM: 0.17ml/kg body weight

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Consideration should also be given to other official guidance on the appropriate use in hepatitis A prophylaxis. For long term hepatitis A prophylaxis, vaccination is recommended

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The medicine is to be administered via the intramuscular route

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Therapy of radiogenic mucositis

• IM: Initial: 10ml (1600mg); After 2 days: 5ml (800mg); After a further 2 days: 5ml (800mg); Treatment can be repeated as often as necessary

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The medicine is to be administered via the intramuscular route

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Method of administration: See additional prescribing points

Paed. forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

The dose and dose regimen are dependent on the indication

Indications for subcutaneous administration (SCIg)

Replacement therapy in:
Primary immunodeficiency syndromes with impaired antibody production
Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia (CLL), in whom prophylactic antibiotics have failed or are contraindicated
Hypogammaglobulinaemia and recurrent bacterial infections in multiple myeloma (MM) patients
Hypogammaglobulinaemia in patients pre- and post-allogeneic haematopoietic stem cell transplantation (HSCT)

• See adult dosage

Indications for intramuscular administration (IMIg)

Hepatitis A prophylaxis
- Pre-exposure prophylaxis, preferably in combination with vaccination, in unvaccinated individuals travelling in less than 2 weeks to areas of hepatitis A risk (short-term prophylaxis)
- Post-exposure prophylaxis in unvaccinated individuals within 2 weeks of hepatitis A virus (HAV) exposure
Therapy of radiogenic mucositis

• See adult dosage

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The posology in children and adolescents (0-18 years) is not different to that of adults as the posology for each indication is given by body weight and adjusted to the clinical outcome in replacement therapy indications

Pregnancy

Recommendations below are applicable to South Africa and other jurisdictions

• Caution
• The safety of human normal immunoglobulin for use in pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women
• Immunoglobulin medicines have been shown to cross the placenta, increasingly during the third trimester
• 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

Breastfeeding

Recommendations below are applicable to South Africa and other jurisdictions

• Caution
• Should only be given with caution in breastfeeding mothers
• Immunoglobulins are excreted into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Subcutaneous Administration

Immune System Disorders

Common ‡

• Hypersensitivity (including blood pressure decrease)

Not known

• Anaphylactic shock/anaphylactic reactions (including dyspnoea, skin reaction)

Nervous System Disorders

Common ‡

• Headache
• Syncope
• Dizziness

Cardiac Disorders

Not known

• Cardiovascular disorders ¶

Vascular Disorders

Not known

• Thromboembolism (including myocardial infarction, ischaemic stroke, deep venous thrombosis, and pulmonary embolism)॥

Respiratory, Thoracic and Mediastinal Disorders

Common ‡

• Bronchospasm

Gastrointestinal Disorders

Not known

• Nausea
• Vomiting

Skin and Subcutaneous Tissue Disorders

Common ‡

• Rash

Musculoskeletal and Connective Tissue Disorders

Common ‡

• Back pain

General Disorders and Administration Site Conditions

Very common

• Injection site pain §
• Injection site swelling
• Erythema
• Induration
• Warmth
• Pruritus
• Bruising
• Rash §

Common ‡

• Pyrexia
• Chills
• Malaise

Not known

• Arthralgia

 ‡ Reported in single cases from clinical study
¶ Cardiovascular disorde r particularly if the medicine has been inadvertently injected intravascularly
॥ Thromboembolism (including myocardial infarction, ischaemic stroke, deep venous thrombosis and pulmonary embolism) has been observed in association with s.c. substitution therapy only
§ In a clinical study with s.c. administration frequency of local reactions at the injection site (including pain, swelling, erythema, warmth, pruritus, bruising, rash) declined very rapidly with the first ten infusions, when patients became used to the s.c. form of treatment
Thromboembolism (including myocardial infarction, ischaemic stroke, deep venous thrombosis and pulmonary embolism) has been observed in association with s.c. substitution therapy only

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Intramuscular Administration

Immune System Disorders

Not known

• Hypersensitivity (including blood pressure decrease)
• Anaphylactic shock/anaphylactic reactions (including dyspnoea, skin reaction)

Nervous System Disorders

Common ‡

• Headache

Not known

• Syncope
• Dizziness

Cardiac Disorders

Not known

• Cardiovascular disorders ¶

Respiratory, Thoracic and Mediastinal Disorders

Not known

• Bronchospasm

Gastrointestinal Disorders

Not known

• Nausea
• Vomiting

Skin and Subcutaneous Tissue Disorders

Not known

• Rash

Musculoskeletal and Connective Tissue Disorders

Not known

• Back pain §

General Disorders and Administration Site Conditions

Very common

• Injection site pain §

Common ‡

• Pyrexia

Not known

• Injection site swelling
• Erythema
• Induration
• Warmth
• Pruritus
• Bruising
• Rash §
• Injection site urticaria †
• Chills
• Malaise
• Arthralgia

‡ Reported in single cases from clinical study
¶ Cardiovascular disorder particularly if the medicine has been inadvertently injected intravascularly
॥ Thromboembolism (including myocardial infarction, ischaemic stroke, deep venous thrombosis and pulmonary embolism) has been observed in association with s.c. substitution therapy only
§ In a clinical study with s.c. administration frequency of local reactions at the injection site (including pain, swelling, erythema, warmth, pruritus, bruising, rash) declined very rapidly with the first ten infusions, when patients became used to the SC form of treatment
† Injection site urticaria has been observed with IM administration only

• Live attenuated vaccines (See additional prescribing points) 

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The listed interactions apply both to adults and children

• Blood pressure (prior to, during, and following infusion)
• Renal function
  - Prior to initial infusion and at appropriate intervals (e.g, patients with pre-existing renal impairment should have sCr measured every 1-3 months, depending on the severity of impairment)
• IgG concentrations
  - SC infusion: For treatment of primary humoral immunodeficiency, monitor IgG trough levels every 2-3 months before/after conversion from IV; subcutaneous infusions provide more constant IgG levels than usual IV immune globulin treatments
• Volume status

Specific cases may require

• Antineutrophil antibodies (if TRALI is suspected)
• Neurologic symptoms (if aseptic meningitis syndrome suspected)
• Haemoglobin or haematocrit prior to and 36 to 96 hours post-infusion and again at 7 to 10 days post-infusion in patients at high risk of haemolysis (dose ≥2g/kg, given as a single dose or divided over several days, and non-O blood type)
• In patients with ITP
  • Urine and urine output
  • Haemoglobin and hematocrit
  • Platelets

Additional observations

• Infusion- or injection-related adverse reactions, anaphylaxis, signs and symptoms of thrombosis, signs and symptoms of haemolysis; blood viscosity (in patients at risk for hyperviscosity such as those with cryoglobulins, fasting chylomicronaemia/severe hypertriglyceridaemia, or monoclonal gammopathies)
• Pulmonary adverse reactions
• Clinical response

Method of administration

For subcutaneous use

• Subcutaneous infusion for home treatment should be initiated and monitored by a physician experienced in home treatment guidance
• Accompany with patient instruction on use of a syringe driver, infusion techniques, keeping a treatment diary, recognising and responding to severe adverse reactions
• Injection sites may include: abdomen, thigh, upper arm and lateral hip
• It is recommended to use an initial administration speed of 10ml/hr/injection site
• If well tolerated, gradually increase speed with each infusion, maximum recommended speed: 22ml/hr per injection site
• More than one injection site can be used simultaneously, infused volume per site may vary
• Infants and children: infusion site may be changed every 5-15ml
• Adults: doses over 30 ml may be divided based on patient preference
• There is no limit to the number of infusion sites

For intramuscular use

• Intramuscular injection must be given by physician or nurse
• Do not inject intravascularly! Note that there is an increased risk of inadvertent intravascular injection in patients who have repeatedly received intramuscular injections

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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 human normal immunoglobulin, 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

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against various 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 donations. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicine may restore abnormally low immunoglobulin G levels to the normal range. Human normal immunoglobulin provides passive transfer of hepatitis A antibodies. The mechanism of action in indications other than replacement therapy and hepatitis A prophylaxis is not fully elucidated, but includes immunomodulatory effects.

Injection (per ml) 160mg

• Beriglobin P (Actor) originator
• Intragam (National Bioproducts Institute)

COMBINATION PREPARATIONS

Human Gammaglobulin/Histamine Dihydrochloride

Injection (per vial) 12mg/0.15μg

• Histaglobin (Mirren) originator