Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Immunoglobulin intravenous - normal (IVIg)

Generic name
Immunoglobulin intravenous - normal (IVIg)
Brand name
ATC Code
J06BA02

Pharmacokinetics in children

After intravenous administration, human normal immunoglobulin is immediately and completely available with relatively rapid distribution to plasma and extravascular fluid. Within approximately 3 to 5 days, a balance is achieved between the intra- and extravascular compartments. IgG and IgG complexes are degraded in the cells of the reticuloendothelial system and are subsequently taken up by the body and incorporated into other proteins or catabolized. Therefore, IgGs are not metabolized by hepatic enzymes or excreted by the kidneys or liver.

No differences in pharmacokinetic properties are expected in pediatric patients. Current evidence shows that the pharmacokinetic profile of pediatric patients (>3 years) is quite similar to that of adults. Data on pharmacokinetics in younger children are lacking

 A summary of the pharmacokinetic (PK) parameters listed in the SmPCs of the licensed products

Age 3-18 years
t½ (days) mean* 33,9
Cmax (g/l) mean 14,2
Vd (l) mean 4,57
Total Cl (l/dag), mean 0,088

* The half-life may vary from patient to patient, especially in primary immunodeficiency.

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dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

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Available formulations

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Dosages

CAUTION:
  • Intravenous
    • 0 years up to 18 years
      [26] [29] [36]
        • Before administration, ensure adequate hydration and urine production.
        • The infusion rates variers per product and therefore the specific product information of each product should be consulted.
          • Start a low infusion rate and increase the rate gradually based on side effects.
Primary immunodeficiency
  • Intravenous
    • Term neonate
      [7]
      • Initial dose: 0.4 - 0.8 g/kg/dose, once only.
      • Maintenance dose: 0.2 - 0.8 g/kg/dose every 3-4 weeks.

      • Aim for normal serum IgG values (> 5-6 g/l), this may need to be adjusted depending on the clinical picture.

    • 1 month up to 18 years
      [7] [21]
      • Initial dose: 0.4 - 0.8 g/kg/dose, once only.
      • Maintenance dose: 0.2 - 0.8 g/kg/dose every 3-4 weeks.

      • Aim for normal serum IgG values (> 5-6 g/l), this may need to be adjusted depending on the clinical picture.
Secondary immune deficiency, hypogammaglobulinaemia after allogenic bone marrow transplant
  • Intravenous
    • Term neonate
      [7]
      • 0.2 - 0.4 g/kg/dose every 3-4 weeks.

      • Aim for normal serum IgG values (> 5-6 g/l), this may need to be adjusted depending on the clinical picture.

         

    • 1 month up to 18 years
      [7] [21]
      • 0.2 - 0.4 g/kg/dose every 3-4 weeks.

      • Aim for normal serum IgG values (> 5-6 g/l), this may need to be adjusted depending on the clinical picture.

         
Guillain-Barré syndrome, agammaglobulinaemia, hypogammaglobulinaemia and other dysimmunoglobulinaemias, autoimmune encephalitis.
Idiopathic thrombocytopenic purpura
  • Intravenous
    • Term neonate
      [7]
      • 0.8 - 1 g/kg/dose, once only.

      • Dose may possibly be repeated after 3 days. Alternative: 0.4 g/kg for 2-5 days.

        Dose in consultation with a haematologist.

    • 1 month up to 18 years
      [7] [21]
      • 0.8 - 1 g/kg/dose, once only.

      • Dose may possibly be repeated after 3 days. Alternative: 0.4 g/kg for 2-5 days.

        Dose in consultation with a haematologist.
Kawasaki disease
  • Intravenous
    • Term neonate
      [2]
      • 2 g/kg/dose, once only.
        • In combination with acetylsalicylic acid.
        • Consider a second dose if necessary.

         

    • 1 month up to 18 years
      [2] [21]
      • 2 g/kg/dose, once only.
        • In combination with acetylsalicylic acid
        • Consider a second dose if necessary.

         
Kawasaki disease with congestive heart failure
  • Intravenous
    • Term neonate
      [2]
      • 1 g/kg/day, continuous infusion.
      • Duration of treatment:

        For 2 days.

    • 1 month up to 18 years
      [2]
      • 1 g/kg/day, continuous infusion.
      • Duration of treatment:

        For 2 days.
Hyperbilirubinaemia caused by blood group antagonism
  • Intravenous
    • Neonates Gestational age ≥ 35 weeks
      [5]
      • 0.5 - 1 g/kg/dose, as required repeat after 12 hours.

      • According to the guidelines in the Netherlands and Belgium, IVIG is no longer recommended for this indication.
Multifocal motor neuropathy (MMN), chronic inflammatory demyelinizing polyneuropathy (CIDP)
  • Intravenous
    • Term neonate
      [6] [9]

      • Initial dose: 2 g/kg split across 2-5 days
        Maintenance dose: 1 g/kg every 2-4 weeks OR 2 g/kg every 4-8 weeks

    • 1 month up to 18 years
      [6] [9] [21]

      • Initial dose: 2 g/kg split across 2-5 days
        Maintenance dose: 1 g/kg every 2-4 weeks OR 2 g/kg every 4-8 weeks
Juvenile dermatomyositis (JDM)
  • Intravenous
    • Term neonate
      [8] [10]
      • 1 g/kg/dose in 12-18 hours on two successive days every month. Alternative: 0.4 g/kg/day on five successive days every month.
      • Duration of treatment:

        For at least 3 months

    • 1 month up to 18 years
      [8] [10]
      • 1 g/kg/dose in 12-18 hours on two successive days every month. Alternative: 0.4 g/kg/day on five successive days every month.
      • Duration of treatment:

        For at least 3 months
Congenital AIDS
  • Intravenous
    • Term neonate
      [6] [9]
      • 0.2 - 0.4 g/kg/dose every 3-4 weeks.
    • 1 month up to 18 years
      [6] [9] [21]
      • 0.2 - 0.4 g/kg/dose every 3-4 weeks.
Vasculitis
Rejection after kidney transplant
  • Intravenous
    • Term neonate
      [15]

      • Little literature is available on the use of immunoglobulins in rejection after kidney transplants. Various dosage schemes are around in the Netherlands, including:  1-2 g/kg one-time only, spread over several days if needed.
        In the study by Billing, 1 g/kg/week was given for 4 weeks (m=20, combined with 1 dose of rituximab).

    • 1 month up to 18 years
      [15]

      • Little literature is available on the use of immunoglobulins in rejection after kidney transplants. Various dosage schemes are around in the Netherlands, including:  1-2 g/kg one-time only, spread over several days if needed.
        In the study by Billing, 1 g/kg/week was given for 4 weeks (m=20, combined with 1 dose of rituximab).
ABO-incompatible kidney transplant
  • Intravenous
    • Term neonate
      [16]
      • 0.5 g/kg/dose, once only.
    • 1 month up to 18 years
      [16]
      • 0.5 g/kg/dose, once only.
Myasthenia gravis (auto-immune)
  • Intravenous
    • Term neonate
      [22]

      • 2 g/kg divided over 2-5 days. 

      • To be repeated based on clinical condition

    • 1 month up to 18 years
      [22]

      • 2 g/kg divided over 2-5 days

      • To be repeated based on clinical condition
Toxic shock syndrome (TSS) and necrotizing fasciitis (NF)
  • Intravenous
    • Term neonate
      [24] [26] [31] [32] [33] [34] [37] [38]
      • 2 g/kg/dose as a single dose.
        • If necessary, consider a second dose of max 2 g/kg on the next day.
        • Alternative treatment: 1 g/kg, day 1, 0.5 g/kg, day 2 and 3 

        There is only limited and inconclusive evidence on the efficacy of IVIG for this indication.

    • 1 month up to 18 years
      [24] [31] [32] [33] [34] [37] [38]
      • 2 g/kg/dose as a single dose.
        • If necessary, consider a second dose of max 2 g/kg on the next day.
        • Alternative treatment: 1 g/kg, day 1, 0.5 g/kg, day 2 and 3 

        There is only limited and inconclusive evidence on the efficacy of IVIG for this indication.
Measles post exposure prophylaxis
  • Intravenous
    • 2 years up to 18 years
      [25]
      • As soon as possible within 6 days of exposure: 0.4 g/kg/day Repeat if needed after 2 weeks based on antibodies (> 240 mI.E./ml ).

      • In PID/SID patients: give as an additional dose within 6 days of exposure, in addition to maintenance therapy.
Measles pre- exposure prophylaxis
  • Intravenous
    • 2 years up to 18 years
      [25]

      • In PID/SID patient receiving a maintenance dose < 0.53 g/kg every 3-4 weeks: increase dose once to 0.53 g/kg. This should yield a serum level > 240 mIE/ml measles antibodies for at least 22 days.

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Renal impaiment in children > 3 months

Cases of acute renal insufficiency have been reported in patients who are on IVIg therapy. In cases of reduced renal function, discontinuing the administration of IVIg should be considered.

In children with a risk of renal impairment, the infusion rate must not be higher than 4.8 ml/kg/hour.

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The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Side effects rarely occur when intravenous immunoglobulins are administered. Fever, problems with joints, nausea, vomiting, infusion reaction and exanthema have been reported. Anaphylactic responses are rare and occur above all in patients with IgA deficiency or antibodies against IgA.

In infants and young children with fructose intolerance (that has not yet been diagnosed), the excipient sorbitol can cause a reaction that can sometimes be fatal. Some types of blood glucose meters incorrectly interpret the excipient maltose as glucose.

The most common side effect in children and adolescents is headache [SmPC Octagam]. After applying maltose containig IVIg glycosuria ocurred in children and adolescents. Maltose is hydrolysed to glucose in renal tubules and gets reabsorbed. Capacity of reabsorbtion is age dependent [SmPC Ig Vena]. Indications for high IVIG doses in children (especially children with Kawasaki disease) are associated with a higher reporting rate of hemolytic reactions [SmPC Privigen].

 

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The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Side effects can largely be prevented by running the infusion in more slowly. An immunologist should be consulted if there are IgA antibodies.

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Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

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Immunoglobulins, normal human
J06BA01
Specific immunoglobulins
J06BB02
IMMUNOGLOBULINS, NORMAL HUMAN
J06BA01

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References

  1. Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2007
  2. Franssen MJAM et al, Werkboek Kinderreumatologie, VU Uitgeverij, 2008, 2e druk
  3. Berg van den, HB et al, Werkboek Kinderhematologie, VU Uitgeverij, 2001, 2e druk
  4. EMA, Guideline on core SmPC for human normal immunoglobulin for IV administration (IVIg), EMA/CHMP/BPWP/94038/2007 rev 3
  5. NVK, Richtlijn preventie, diagnostiek en behandeling van hyperbilirubinemie bijde pasgeborene, geboren na een zwangerschapsduur van meer dan 35 weken, www.nvk.nl, 2008, http://www.nvk.nl/Kwaliteit/Richtlijnenenindicatoren/Richtlijnen.aspx
  6. Takeda Manufacturing Austria AG, SmPC Kiovig (EU/1/05/329/001-006) Rev 26, 27-06-2022, www.ema.europa.eu
  7. Baxalta Innovations GmbH., SmPC Gammagard S/D 5/10 g, poeder en oplosmiddel voor oplossing voor infusie (RVG 17033/17034). 27-01-2023, www.geneesmiddeleninformatiebank.nl
  8. CBO. , Richtlijn dermatomyositis, polymyositis en sporadische ‘inclusion body’-myositis., www.diliguide.nl , 2004
  9. Grifols Deutschland GmbH. , SPC Gamunex (RVG 33687) 11-2-2015., www.geneesmiddeleninformatiebank.nl
  10. Reed AM et al. , Juvenile dermatomyositis: recognition and treatment., Paediatr Drugs., 2002, 4(5), 315-21
  11. Adlakha A et al. , A case of pediatric Wegener's granulomatosis with recurrent venous thromboses treated with intravenous immunoglobulin and laryngotracheoplasty., Pediatr Pulmonol. , 1995 , Oct;20(4):, 265-8
  12. Finkel TH et al. , Chronic parvovirus B19 infection and systemic necrotising vasculitis: opportunistic infection or aetiological agent., Lancet. , 1994 , May 21;343(8908):, 1255-8
  13. Han SB et al. , Bilateral exudative retinal detachment in Churg-Strauss syndrome controlled with intravenous immunoglobulin., Jpn J Ophthalmol., 2010 , May;54(3):, 250-2
  14. Taylor CT et al. , Treatment of Wegener's granulomatosis with immune globulin: CNS involvement in an adolescent female., Ann Pharmacother. , 1999 , Oct;33(10), 1055-9
  15. Billing H et al. , IVIG and rituximab for treatment of chronic antibody-mediated rejection: a prospective study in paediatric renal transplantation with a 2-year follow-up., Transpl Int. , 2012 , Nov;25(11), 1165-73
  16. Tydén G et al. , ABO-incompatible kidney transplantation in children., Pediatr Transplant. , 2011 , Aug;15(5):, 502-4
  17. Titulaer MJ et al, Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study., Lancet Neurol, 2013 , Feb;12(2), 157-65
  18. Byrne S, Earlier treatment of NMDAR antibody encephalitis in children results in a better outcome., Neurol Neuroimmunol Neuroinflamm, 2015, Jul 23;2(4), e130
  19. Kedrion, SmPC Ig Vena 50 g/L Inf.lsg. (2-00321), https://www.univadis.at/, 10/2018
  20. CSL Behring, SmPC Privigen 100 mg/ml Inf.lsg. (EU/1/08/446/001-007) Rev 31, 15-06-2023, www.ema.europa.eu
  21. Octapharma, SmPC Octagam 5% Inf.lsg. (2-38569), https://www.univadis.at/, 12/2018
  22. Sanders, DB et al, International consensus guidance for management of myasthenia gravis, Neurology, 2016, 87, 419-25
  23. Prothya Biosolutions Netherlands B.V, SmPC Nanogam 50 mg/ml oplossing voor infusie (RVG 31627) 19-10-2021, www.geneesmiddeleninformatiebank.nl
  24. Bustos BR, et al. , [Necrotizing fasciitis of the eyelids and toxic shock syndrome due to Streptococcus pyogenes]. , Rev Chilena Infectol., 2009, 26(2), 152-5
  25. Instituto Grifols, S.A. , SmPC Flebogamma DIF, 50 mg/ml oplossing voor infusie (EU/1/07/404/001—005). Rev 19, 11-01-2024, www.ema.europa.eu
  26. Ibis IBP, et al., Adverse reactions and influencing factors in children with primary immunodeficiencies receiving intravenous immunglobulin replacement., Allergol Immunopathol (Madr), 2020, 48(6), 738-44
  27. Kriván G, et al., An open, prospective trial investigating the pharmacokinetics and safety, and the tolerability of escalating infusion rates of a 10% human normal immunoglobulin for intravenous infusion (IVIg), BT090, in patients with primary immunodeficiency disease., Vox Sang, 2015, 109(3), 248-56
  28. Octapharma GmbH. , SmPC Octagam 50 mg/ml, oplossing voor infusie (RVG 123226). 11-5-2023. , www.geneesmiddeleninformatiebank.nl
  29. Malaki M., Considerations for Intravenous Immunoglobulin Infusion in Neonates., Journal of Clinical Neonatology, 2021, 10(4), 255-6
  30. Biotest Pharma GmbH. , SmPC Intratect 50 g/l oplossing voor infusie (RVG 32712). 28-05-2023, www.geneesmiddeleninformatiebank.nl
  31. Chen KY, et al., Toxic shock syndrome in Australian children., Arch Dis Child, 2016, 101(8), 736-40
  32. Gottlieb M, et al, The Evaluation and Management of Toxic Shock Syndrome in the Emergency Department: A Review of the Literature., J Emerg Med, 2018, 54(6), 807-14
  33. Powell C, et al, Toxic shock syndrome in a neonate., Pediatr Infect Dis J., 2007, 26(8), 759-60
  34. Huang YC, et al. , A family cluster of streptococcal toxic shock syndrome in children: clinical implication and epidemiological investigation., Pediatrics, 2001, 107(5), 1181-3
  35. Kedrion S.P.A., Ig Vena 50 g/l solution for infusion. Last updated 2-2010., http://www.biogenetech.co.th/wp-content/uploads/2011/10/IgVena_PI0605_E1002_rev.01.pdf
  36. Figueras-Aloy J, et al., Intravenous immunoglobulin and necrotizing enterocolitis in newborns with hemolytic disease. , Pediatrics, 2010, 125(1), 139-44
  37. Stichting Werkgroep Antibioticabeleid (SWAB). , Toxic Shock Syndrome, 276213, Last updated 8-25-2018
  38. Stichting Werkgroep Antibioticabeleid (SWAB). , Fasciitis necroticans, https://children.nl.antibiotica.app/nl/node/273813, Last updated 8-25-2018

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Changes

Changes